G2Cdb::Gene report

Gene id
G00000328
Gene symbol
Bsg (MGI)
Species
Mus musculus
Description
basigin
Orthologue
G00001577 (Homo sapiens)

Databases (10)

Gene
ENSMUSG00000023175 (Ensembl mouse gene)
12215 (Entrez Gene)
664 (G2Cdb plasticity & disease)
Gene Expression
NM_009768 (Allen Brain Atlas)
g03819 (BGEM)
12215 (Genepaint)
bsg (gensat)
Literature
109480 (OMIM)
Marker Symbol
MGI:88208 (MGI)
Protein Sequence
P18572 (UniProt)

Synonyms (6)

  • 5A11/Basigin
  • CD147
  • EMMPRIN
  • HT-7
  • gp 42
  • neurothelin

Literature (81)

Pubmed - other

  • Basigin/CD147 promotes renal fibrosis after unilateral ureteral obstruction.

    Kato N, Kosugi T, Sato W, Ishimoto T, Kojima H, Sato Y, Sakamoto K, Maruyama S, Yuzawa Y, Matsuo S and Kadomatsu K

    Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan.

    Regardless of their primary causes, progressive renal fibrosis and tubular atrophy are the main predictors of progression to end-stage renal disease. Basigin/CD147 is a multifunctional molecule-it induces matrix metalloproteinases and hyaluronan, for example-and has been implicated in organ fibrosis. However, the relationship between basigin and organ fibrosis has been poorly studied. We investigated basigin's role in renal fibrosis using a unilateral ureteral obstruction model. Basigin-deficient mice (Bsg(-/-)) demonstrated significantly less fibrosis after surgery than Bsg(+/+) mice. Fewer macrophages had infiltrated in Bsg(-/-) kidneys. Consistent with these in vivo data, primary cultured tubular epithelial cells from Bsg(-/-) mice produced less matrix metalloproteinase and exhibited less motility on stimulation with transforming growth factor β. Furthermore, Bsg(-/-) embryonic fibro blasts produced less hyaluronan and α-smooth muscle actin after transforming growth factor β stimulation. Together, these results demonstrate for the first time that basigin is a key regulator of renal fibrosis. Basigin could be a candidate target molecule for the prevention of organ fibrosis.

    The American journal of pathology 2011;178;2;572-9

  • A high-resolution anatomical atlas of the transcriptome in the mouse embryo.

    Diez-Roux G, Banfi S, Sultan M, Geffers L, Anand S, Rozado D, Magen A, Canidio E, Pagani M, Peluso I, Lin-Marq N, Koch M, Bilio M, Cantiello I, Verde R, De Masi C, Bianchi SA, Cicchini J, Perroud E, Mehmeti S, Dagand E, Schrinner S, Nürnberger A, Schmidt K, Metz K, Zwingmann C, Brieske N, Springer C, Hernandez AM, Herzog S, Grabbe F, Sieverding C, Fischer B, Schrader K, Brockmeyer M, Dettmer S, Helbig C, Alunni V, Battaini MA, Mura C, Henrichsen CN, Garcia-Lopez R, Echevarria D, Puelles E, Garcia-Calero E, Kruse S, Uhr M, Kauck C, Feng G, Milyaev N, Ong CK, Kumar L, Lam M, Semple CA, Gyenesei A, Mundlos S, Radelof U, Lehrach H, Sarmientos P, Reymond A, Davidson DR, Dollé P, Antonarakis SE, Yaspo ML, Martinez S, Baldock RA, Eichele G and Ballabio A

    Telethon Institute of Genetics and Medicine, Naples, Italy.

    Ascertaining when and where genes are expressed is of crucial importance to understanding or predicting the physiological role of genes and proteins and how they interact to form the complex networks that underlie organ development and function. It is, therefore, crucial to determine on a genome-wide level, the spatio-temporal gene expression profiles at cellular resolution. This information is provided by colorimetric RNA in situ hybridization that can elucidate expression of genes in their native context and does so at cellular resolution. We generated what is to our knowledge the first genome-wide transcriptome atlas by RNA in situ hybridization of an entire mammalian organism, the developing mouse at embryonic day 14.5. This digital transcriptome atlas, the Eurexpress atlas (http://www.eurexpress.org), consists of a searchable database of annotated images that can be interactively viewed. We generated anatomy-based expression profiles for over 18,000 coding genes and over 400 microRNAs. We identified 1,002 tissue-specific genes that are a source of novel tissue-specific markers for 37 different anatomical structures. The quality and the resolution of the data revealed novel molecular domains for several developing structures, such as the telencephalon, a novel organization for the hypothalamus, and insight on the Wnt network involved in renal epithelial differentiation during kidney development. The digital transcriptome atlas is a powerful resource to determine co-expression of genes, to identify cell populations and lineages, and to identify functional associations between genes relevant to development and disease.

    Funded by: Medical Research Council: MC_U127527203; Telethon: TGM11S03

    PLoS biology 2011;9;1;e1000582

  • EMMPRIN: a novel regulator of leukocyte transmigration into the CNS in multiple sclerosis and experimental autoimmune encephalomyelitis.

    Agrawal SM, Silva C, Tourtellotte WW and Yong VW

    Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.

    Extracellular matrix metalloproteinase inducer (EMMPRIN, CD147) is a member of the Ig superfamily, with various physiological roles including the induction of matrix metalloproteinases (MMPs), leukocyte activation, and tumor progression. In this study, we illustrate a novel involvement of EMMPRIN in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). We found EMMPRIN levels to be upregulated on peripheral leukocytes before onset of EAE clinical signs and on infiltrating leukocytes and resident cells within the CNS in symptomatic mice. In EAE brain sections, EMMPRIN expression was localized with MMP-9 protein and activity. The increased EMMPRIN level was also characteristic of brain samples from MS subjects, particularly in plaque-containing areas. To evaluate the implications of elevated EMMPRIN levels, we treated EAE mice with an EMMPRIN function-blocking antibody and found reduced EAE clinical severity accompanied by decreased CNS parenchymal infiltration of leukocytes. Amelioration of EAE clinical signs by the anti-EMMPRIN antibody was critically dependent on its administration around the period of onset of clinical signs, which is typically associated with significant influx of leukocytes into the CNS. Moreover, the reduction in disease severity in anti-EMMPRIN-treated mice was associated with diminished MMP proteolytic activity at the glia limitans, the final barrier before parenchymal infiltration of leukocytes. Together, our results are the first to emphasize a role for EMMPRIN in MS and EAE, whereby EMMPRIN regulates leukocyte trafficking through increasing MMP activity. These results identify EMMPRIN as a novel therapeutic target in MS.

    Funded by: Canadian Institutes of Health Research

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2011;31;2;669-77

  • EMMPRIN activates multiple transcription factors in cardiomyocytes, and induces interleukin-18 expression via Rac1-dependent PI3K/Akt/IKK/NF-kappaB andMKK7/JNK/AP-1 signaling.

    Venkatesan B, Valente AJ, Prabhu SD, Shanmugam P, Delafontaine P and Chandrasekar B

    Research Service, Southeast Louisiana Veterans Health Care System, New Orleans, LA 70161, USA.

    The transmembrane glycoprotein extracellular matrix metalloproteinase inducer (EMMPRIN), and the pleiotropic proinflammatory cytokine interleukin (IL)-18, play critical roles in myocardial remodeling, by inducing matrix degrading metalloproteinases (MMPs). Previously we showed that IL-18 induces EMMPRIN expression in cardiomyocytes via MyD88/IRAK4/TRAF6/JNK-dependent Sp1 activation. Here in reciprocal studies we demonstrate that EMMPRIN is a potent inducer of IL-18 transcription, protein expression and protein secretion in primary mouse cardiomyocytes. We show for the first time that EMMPRIN stimulates the activation of NF-kappaB, AP-1, CREB, and ATF-2 in cardiomyocytes, and induces IL-18 expression via Rac1-dependent PI3K/Akt/IKK/NF-kappaB and MKK7/JNK/AP-1 signaling. Moreover, EMMPRIN induces robust time-dependent induction of various MMP mRNAs. EMMPRIN also induces the mRNA of TIMPs 1 and 3, but in a delayed fashion. These results suggest that IL-18-induced EMMPRIN expression may favor net MMP expression and ECM destruction, and thus identify both as potential therapeutic targets in countering adverse myocardial remodeling.

    Funded by: NHLBI NIH HHS: HL-70241, HL-80682, HL-86787, R01 HL070241, R01 HL080682, R01 HL086787, R01 HL099014

    Journal of molecular and cellular cardiology 2010;49;4;655-63

  • Interleukin-18 induces EMMPRIN expression in primary cardiomyocytes via JNK/Sp1 signaling and MMP-9 in part via EMMPRIN and through AP-1 and NF-kappaB activation.

    Reddy VS, Prabhu SD, Mummidi S, Valente AJ, Venkatesan B, Shanmugam P, Delafontaine P and Chandrasekar B

    Cardiothoracic Surgery, University of Texas Health Science Center, San Antonio, Texas, USA.

    IL-18 and the extracellular matrix metalloproteinase (MMP) inducer (EMMPRIN) stimulate the expression of proinflammatory cytokines and MMPs and are elevated in myocardial hypertrophy, remodeling, and failure. Here, we report several novel findings in primary cardiomyocytes treated with IL-18. First, IL-18 activated multiple transcription factors, including NF-κB (p50 and p65), activator protein (AP)-1 (cFos, cJun, and JunD), GATA, CCAAT/enhancer-binding protein, myocyte-specific enhancer-binding factor, interferon regulatory factor-1, p53, and specific protein (Sp)-1. Second, IL-18 induced EMMPRIN expression via myeloid differentiation primary response gene 88/IL-1 receptor-associated kinase/TNF receptor-associated factor-6/JNK-dependent Sp1 activation. Third, IL-18 induced a number of MMP genes, particularly MMP-9, at a rapid rate as well as tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-3 at a slower rate. Finally, the IL-18 induction of MMP-9 was mediated in part via EMMPRIN and through JNK- and ERK-dependent AP-1 activation and p38 MAPK-dependent NF-κB activation. These results suggest that the elevated expression of IL-18 during myocardial injury and inflammation may favor EMMPRIN and MMP induction and extracellular matrix degradation. Therefore, targeting IL-18 or its signaling pathways may be of potential therapeutic benefit in adverse remodeling.

    Funded by: NHLBI NIH HHS: HL-70241, HL-80682, HL-86787, R01 HL086787, R01 HL099014

    American journal of physiology. Heart and circulatory physiology 2010;299;4;H1242-54

  • Localization of members of MCT monocarboxylate transporter family Slc16 in the kidney and regulation during metabolic acidosis.

    Becker HM, Mohebbi N, Perna A, Ganapathy V, Capasso G and Wagner CA

    Institute of Physiology and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.

    The monocarboxylate transporter family (MCT) comprises 14 members with distinct transport properties and tissue distribution. The kidney expresses several members of the MCT family, but only little is known about their exact distribution and function. Here, we investigated selected members of the MCT family in the mouse kidney. MCT1, MCT2, MCT7, and MCT8 localized to basolateral membranes of the epithelial cells lining the nephron. MCT1 and MCT8 were detected in proximal tubule cells whereas MCT7 and MCT2 were located in the thick ascending limb and the distal tubule. CD147, a beta-subunit of MCT1 and MCT4, showed partially overlapping expression with MCT1 and MCT2. However, CD147 was also found in intercalated cells. We also detected SMCT1 and SMCT2, two Na(+)-dependent monocarboxylate cotransporters, on the luminal membrane of type A intercalated cells. Moreover, mice were given an acid load for 2 and 7 days. Acidotic animals showed a marked but transient increase in urinary lactate excretion. During acidosis, a downregulation of MCT1, MCT8, and SMCT2 was observed at the mRNA level, whereas MCT7 and SMCT1 showed increased mRNA abundance. Only MCT7 showed lower protein abundance whereas all other transporters remained unchanged. In summary, we describe for the first time the localization of various MCT transporters in mammalian kidney and demonstrate that metabolic acidosis induces a transient increase in urinary lactate excretion paralleled by lower MCT7 protein expression.

    American journal of physiology. Renal physiology 2010;299;1;F141-54

  • Expression of basigin in reproductive tissues of estrogen receptor-{alpha} or -{beta} null mice.

    Chen L, Bi J, Nakai M, Bunick D, Couse JF, Korach KS and Nowak RA

    Departments of Animal Sciences Veterinary Biosciences, University of Illinois, Urbana, Illinois 61801, USA.

    Basigin plays important roles in both male and female reproduction because basigin (Bsg) null male and female mice are infertile. The aim of the present study was to determine whether basigin expression in reproductive organs requires estrogen receptor-alpha (ESR1, ERalpha) or -beta (ESR2, ERbeta). Expression of basigin protein in the testis, ovary, and male and female reproductive tracts was studied in adult wild-type (WT), Esr1-null (alphaERKO), and Esr2-null (betaERKO) mice by immunohistochemistry and immunoblotting. Basigin mRNA levels in ovary and uterus were examined by quantitative RT-PCR. In females, basigin protein expression was observed mainly in granulosa and interstitial cells of the ovary and epithelial cells of the proximal oviduct in all genotypes. Basigin protein was also expressed in the uterine epithelium at proestrus and estrus in WT and betaERKO mice but not in alphaERKO mice. However, a higher level of basigin mRNA was observed in uteri of alphaERKO mice compared with WT and betaERKO mice. In males, basigin was expressed in Leydig cells and all germ cells except spermatogonia in all genotypes. Basigin was present in epithelial cells lining the efferent ductules in WT and betaERKO mice, but expression was greatly reduced in alphaERKO mice. In epididymal ducts, basigin expression was observed in epithelial cells in the caput and cauda in all genotypes. These data suggest that expression of basigin protein requires ESR1, but not ESR2, in the uterus and efferent ductules, but is independent of estrogen receptor in the ovary, oviduct, testis, and epididymis.

    Funded by: Intramural NIH HHS: Z01 ES070065-31; NICHD NIH HHS: U54 HD040093, U54 HD40093

    Reproduction (Cambridge, England) 2010;139;6;1057-66

  • EMMPRIN (basigin/CD147) is involved in the morphogenesis of tooth germ in mouse molars.

    Xie M, Jiao T, Chen Y, Xu C, Li J, Jiang X and Zhang F

    Shanghai Key Laboratory of Stomatology, Department of Prosthodontics, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, China. hookxie@126.com

    The pattern of gene expression for extracellular matrix metalloproteinase inducer (EMMPRIN) was revealed in the tooth germ of mouse mandibular molars using quantitative real-time PCR. In situ hybridization and immunohistochemical study demonstrated the characteristic distribution of EMMPRIN in the different stages of tooth germ development. To investigate the functional role played by EMMPRIN in tooth germ development, EMMPRIN siRNA interference approach was carried out in cultured mouse mandibles at embryonic day 11.0 (E11.0). The results showed that EMMPRIN siRNA-treated explants exhibited a marked growth inhibition of tooth germ compared to the control and scrambled siRNA-treated explants. Meanwhile, a significant increase in MT1-MMP mRNA expression and a reduction in MMP-2, MMP-3, MMP-9, MMP-13 and MT2-MMP mRNA expression were observed in the mouse mandibles following EMMPRIN abrogation. The current results indicate that EMMPRIN could thus be involved in the early stage of tooth germ development and morphogenesis, possibly by regulating the expression of MMP genes.

    Histochemistry and cell biology 2010;133;5;585-94

  • The annulus of the mouse sperm tail is required to establish a membrane diffusion barrier that is engaged during the late steps of spermiogenesis.

    Kwitny S, Klaus AV and Hunnicutt GR

    Population Council, Center for Biomedical Research, Rockefeller University, New York, NY 10065, USA.

    The annulus is a higher order septin cytoskeletal structure located between the midpiece and principal piece regions of the sperm tail. The annulus has been hypothesized to generate the diffusion barrier that exists between these two membrane domains. We tested this premise directly on septin 4 knockout mice, whose sperm are viable but lack an annulus, by following the diffusing membrane protein basigin. Basigin is normally confined to the principal piece domain on testicular and caput sperm, but undergoes relocation into the midpiece during sperm epididymal transit. On Sept4(-/-) sperm, domain confinement was lost, and basigin localized over the entire plasma membrane. Both immunofluorescence and immunoblotting further revealed reduced levels of basigin expression on sperm from the knockout. Testicular immunohistochemistry showed similar basigin expression and tail targeting in wild-type (WT) and Sept4(-/-) tubules until step 15 of spermatid development, at which point basigin was redistributed throughout the plasma membrane of Sept4(-/-) spermatids. The basigin outside of the tail was subsequently lost around the time of sperm release into the lumen. The redistribution in the knockout coincides with the time in WT sperm when the annulus completes its migration from the neck down to the midpiece-principal piece junction. We posit that basigin may not diffuse freely until after the annulus arrives at the midpiece-principal piece junction to restrict lateral movement. These results are the strongest evidence to date of a mammalian septin structure establishing a membrane diffusion barrier.

    Funded by: NICHD NIH HHS: HD038807, R01 HD038807

    Biology of reproduction 2010;82;4;669-78

  • EMMPRIN and its ligand cyclophilin A regulate MT1-MMP, MMP-9 and M-CSF during foam cell formation.

    Seizer P, Schönberger T, Schött M, Lang MR, Langer HF, Bigalke B, Krämer BF, Borst O, Daub K, Heidenreich O, Schmidt R, Lindemann S, Herouy Y, Gawaz M and May AE

    Medizinische Klinik III, Eberhard Karls University Tuebingen, Germany.

    Unlabelled: Upon coincubation with platelets, CD34(+) progenitor cells have the potential to differentiate into foam cells, and thereby may promote the progression of atherosclerosis. The exact mechanism of MMP-regulation during the cellular differentiation process to foam cells is still unclear. Thus, we investigated the role of EMMPRIN (CD147) and its ligand cyclophilin A (CyPA) during foam cell formation originating from both monocytes/macrophages and CD34(+) progenitor cells.

    Differentiation of CD34(+) progenitor to foam cells was analyzed in a coculture model of progenitor cells and platelets. While CD34(+) cells did not express EMMPRIN or MT1-MMP, mature foam cells strongly expressed EMMPRIN, which was associated with MT1-MMP expression as well as MMP-9. Gene silencing of EMMPRIN by siRNA during the cell differentiation process hindered not only the upregulation of MMPs (MT1-MMP, MMP-9), but also the secretion of the cytokine M-CSF. During the differentiation process CyPA was substantially released into the supernatant. The presence of the CyPA inhibitor NIM811 significantly reduced MMP-9 secretion during the differentiation process. Similar results were obtained using the classical pathway of foam cell formation by coincubating human macrophages with AcLDL. Additionally, the presence of soluble EMMPRIN ligands (CyPA, recombinant EMMPRIN) further enhanced MMP-9 secretion by mature foam cells. Consistently, CyPA and EMMPRIN were found in atherosclerotic plaques of ApoE-deficient mice by immunohistochemistry.

    Conclusion: EMMPRIN is upregulated during the differentiation process from CD34(+) progenitor cells to foam cells, whereas its ligand, CyPA, is released. The CyPA/EMMPRIN activation pathway may play a relevant role in promoting the vulnerability of atherosclerotic plaques.

    Atherosclerosis 2010;209;1;51-7

  • Hydrophobic interactions stabilize the basigin-MCT1 complex.

    Finch NA, Linser PJ and Ochrietor JD

    Department of Biology, University of North Florida, 1 UNF Drive, Jacksonville, FL, 32224, USA.

    Previous reports demonstrated that monocarboxylate transporter-1 (MCT1) interacts with Basigin. It was hypothesized that the two proteins interact via the transmembrane domain of Basigin, specifically through the glutamate residue within the domain. We therefore sought to test this hypothesis and determine which amino acids of the Basigin protein are necessary for the interaction with MCT1. Probes consisting of the full-length putative transmembrane domain, as well as small regions of the domain, were generated for use in ELISA binding assays using endogenous mouse MCT1. Site directed mutagenesis of candidate residues was performed and probes were generated for ELISA analyses to determine the specific residues involved. The data suggest that hydrophobic residues at the N- and C-termini of the putative transmembrane domain of Basigin interact with MCT1, but the glutamate plays no role. The previously proposed hypothesis is partially correct, in that the putative transmembrane domain of Basigin does interact with MCT1.

    Funded by: NEI NIH HHS: F32EY13918

    The protein journal 2009;28;7-8;362-8

  • Nitric oxide induces the progression of abdominal aortic aneurysms through the matrix metalloproteinase inducer EMMPRIN.

    Lizarbe TR, Tarín C, Gómez M, Lavin B, Aracil E, Orte LM and Zaragoza C

    Institutional Fundación Centro Nacional de Investigaciones Cardiovasculares, Madrid 28029, Spain.

    Nitric Oxide (NO) is involved in the development and progression of abdominal aortic aneurysms (AAA). We found that inhibition of inducible NO synthase (iNOS) protects mice in an elastase-induced AAA model, significantly inhibiting the production of matrix metalloproteinase-13 (MMP-13). The extracellular MMP inducer (EMMPRIN; CD147) was increased in human AAA biopsies and in wild-type murine AAA but not in AAA from iNOS null mice. In cells overexpressing ectopic EMMPRIN, MMP-13 secretion was stimulated, whereas silencing of EMMPRIN by RNA interference led to significant inhibition of MMP-13 expression. In addition, elastase infusion of MMP-13 null mouse aortas induced a significant increase of EMMPRIN but reduced aortic dilatation when compared with wild-type mice, suggesting that NO-mediated AAA may be mediated through EMMPRIN induction of MMP-13. These findings were further verified in elastase-infused iNOS null mice, in which daily administration of NO caused a significant aortic dilatation and the expression of EMMPRIN and MMP-13. By contrast, in iNOS wild-type mice, pharmacological inhibition of iNOS by administration of 1400 W induced a reduction of aortic diameter and inhibition of MMP-13 and EMMPRIN expression when compared with control mice. Our results suggest that NO may regulate the development of AAA in part by inducing the expression of EMMPRIN and modulating the activity of MMP-13 in murine and human aneurysms.

    The American journal of pathology 2009;175;4;1421-30

  • Silencing CD147 inhibits tumor progression and increases chemosensitivity in murine lymphoid neoplasm P388D1 cells.

    Jia L, Wei W, Cao J, Xu H, Miao X and Zhang J

    Department of Biochemistry, Institute of Glycobiology, Dalian Medical University, Dalian, Liaoning Province, China.

    Overexpression of extracellular matrix metalloproteinase inducer (EMMPRIN or CD147), a member glycoprotein enriched on the surface of many malignant tumor cells, promotes tumor progression and confers resistance to some chemotherapeutic drugs. To investigate the possible role of CD147 in the macrophage-like lymphoid neoplasm P388D1 cells progression, we used RNA interference approach to silence CD147 expression. The results showed that silencing of CD147 in P388D1 cells impeded the expression of MMP11 at both mRNA and protein levels. The reduced CD147 expression also resulted in reductions in tumorigenicity, as well as decreased in regional lymph node metastasis. Furthermore, the down-regulation of CD147 expression sensitized cells to be more sensitive to chemotherapeutic drugs. Treatment of tumor cells with U-0126, an inhibitor of mitogen-activated protein kinase/Erk, also down-regulated the expression of MMP11. Our current results indicate that the expression of CD147 functionally mediates tumor progression and is a potential target for therapeutic anti-cancer drugs.

    Annals of hematology 2009;88;8;753-60

  • The E-selectin ligand basigin/CD147 is responsible for neutrophil recruitment in renal ischemia/reperfusion.

    Kato N, Yuzawa Y, Kosugi T, Hobo A, Sato W, Miwa Y, Sakamoto K, Matsuo S and Kadomatsu K

    Department of Biochemistry, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan.

    E-selectin and its ligands are essential for extravasation of leukocytes in inflammation. Here, we report that basigin (Bsg)/CD147 is a ligand for E-selectin that promotes renal inflammation in ischemia/reperfusion. Compared with wild-type mice, Bsg-deficient (Bsg(-/-)) mice demonstrated striking suppression of neutrophil infiltration in the kidney after renal ischemia/reperfusion. Although E-selectin expression increased similarly between the two genotypes, Bsg(-/-) mice exhibited less renal damage, suggesting that Bsg on neutrophils contribute to renal injury in this model. Neutrophils expressed Bsg with N-linked polylactosamine chains and Bsg(-)(/)(-) neutrophils showed reduced binding to E-selectin. Bsg isolated from HL-60 cells bound to E-selectin, and tunicamycin treatment to abolish N-linked glycans from Bsg abrogated this binding. Furthermore, Bsg(-)(/)(-) neutrophils exhibited reduced E-selectin-dependent adherence to human umbilical vein endothelial cells in vitro. Injection of labeled neutrophils into mice showed that Bsg(-)(/)(-) neutrophils were less readily recruited to the kidney after renal ischemia/reperfusion than Bsg(+/+) neutrophils, regardless of the recipient's genotype. Taken together, these results indicate that Bsg is a physiologic ligand for E-selectin that plays a critical role in the renal damage induced by ischemia/reperfusion.

    Journal of the American Society of Nephrology : JASN 2009;20;7;1565-76

  • The level of the transcription factor Pax6 is essential for controlling the balance between neural stem cell self-renewal and neurogenesis.

    Sansom SN, Griffiths DS, Faedo A, Kleinjan DJ, Ruan Y, Smith J, van Heyningen V, Rubenstein JL and Livesey FJ

    Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK.

    Neural stem cell self-renewal, neurogenesis, and cell fate determination are processes that control the generation of specific classes of neurons at the correct place and time. The transcription factor Pax6 is essential for neural stem cell proliferation, multipotency, and neurogenesis in many regions of the central nervous system, including the cerebral cortex. We used Pax6 as an entry point to define the cellular networks controlling neural stem cell self-renewal and neurogenesis in stem cells of the developing mouse cerebral cortex. We identified the genomic binding locations of Pax6 in neocortical stem cells during normal development and ascertained the functional significance of genes that we found to be regulated by Pax6, finding that Pax6 positively and directly regulates cohorts of genes that promote neural stem cell self-renewal, basal progenitor cell genesis, and neurogenesis. Notably, we defined a core network regulating neocortical stem cell decision-making in which Pax6 interacts with three other regulators of neurogenesis, Neurog2, Ascl1, and Hes1. Analyses of the biological function of Pax6 in neural stem cells through phenotypic analyses of Pax6 gain- and loss-of-function mutant cortices demonstrated that the Pax6-regulated networks operating in neural stem cells are highly dosage sensitive. Increasing Pax6 levels drives the system towards neurogenesis and basal progenitor cell genesis by increasing expression of a cohort of basal progenitor cell determinants, including the key transcription factor Eomes/Tbr2, and thus towards neurogenesis at the expense of self-renewal. Removing Pax6 reduces cortical stem cell self-renewal by decreasing expression of key cell cycle regulators, resulting in excess early neurogenesis. We find that the relative levels of Pax6, Hes1, and Neurog2 are key determinants of a dynamic network that controls whether neural stem cells self-renew, generate cortical neurons, or generate basal progenitor cells, a mechanism that has marked parallels with the transcriptional control of embryonic stem cell self-renewal.

    Funded by: Cancer Research UK; Medical Research Council: MC_U127527199; NINDS NIH HHS: R01 NS034661, R01 NS099099; Wellcome Trust

    PLoS genetics 2009;5;6;e1000511

  • Localization of low-density detergent-resistant membrane proteins in intact and acrosome-reacted mouse sperm.

    Miranda PV, Allaire A, Sosnik J and Visconti PE

    Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA, USA.

    Mammalian sperm become fertile after completing capacitation, a process associated with cholesterol loss and changes in the biophysical properties of the sperm membranes that prepares the sperm to undergo the acrosome reaction. Different laboratories have hypothesized that cholesterol efflux can influence the extent and/or movement of lipid raft microdomains. In a previous study, our laboratory investigated the identity of sperm proteins putatively associated with rafts. After extraction with Triton X-100 and ultracentrifugation in sucrose gradients, proteins distributing to the light buoyant-density fractions were cored from polyacrylamide gels and microsequenced. In this study, a subset of these proteins (TEX101, basigin, hexokinase 1, facilitated glucose transporter 3, IZUMO, and SPAM1) and other molecules known to be enriched in membrane rafts (caveolin 2, flotillin 1, flotillin 2, and the ganglioside GM3) were selected to investigate their localization in the sperm and their behavior during capacitation and the acrosome reaction. These molecules localize to multiple sperm domains, including the acrosomal cap (IZUMO, caveolin 2, and flotillin 2), equatorial segment (GM3), cytoplasmic droplet (TEX101), midpiece (basigin, facilitated glucose transporter 3, and flotillin 2), and principal piece (facilitated glucose transporter 3). Some of these markers modified their immunofluorescence pattern after sperm incubation under capacitating conditions, and these changes correlated with the occurrence of the acrosome reaction. While GM3 and caveolin 2 were not detected after the acrosome reaction, flotillin 2 was found in the equatorial segment of acrosome-reacted sperm, and IZUMO distributed along the sperm head, reaching the post- and para-acrosomal areas. Taking into consideration the requirement of the acrosome reaction for sperm to become fusogenic, these results suggest that membrane raft dynamics may have a role in sperm-egg membrane interaction.

    Funded by: NICHD NIH HHS: HD38082, HD44044, R01 HD038082, R01 HD044044

    Biology of reproduction 2009;80;5;897-904

  • CD147 impacts angiogenesis and metastasis formation.

    Voigt H, Vetter-Kauczok CS, Schrama D, Hofmann UB, Becker JC and Houben R

    Department of Dermatology, Julius-Maximilians-University, Würzburg, Germany.

    CD147 is highly expressed on many tumor cells; its role for tumor invasiveness and metastasis has been deduced from its capacity to induce MMPs, i.e., MMP-1, -2, -3, and -9. However, in the murine B16 melanoma model, MMP-2/-9 expression occurs independent of CD147. To scrutinize the impact of CD147 on metastasis formation and angiogenesis in this model, CD147 was stably knocked down in B16 cells. This silencing of CD147 expression resulted in a reduced capability of the tumor cells to metastasize to the draining lymph nodes. Notably, the CD147 knock down caused a decreased VEGF expression in vivo accompanied by reduced blood vessel formation. Thus, in the B16 melanoma model, CD147 promotes metastasis formation by induction of angiogenesis in an MMP independent manner.

    Cancer investigation 2009;27;3;329-33

  • Basigin-mediated gene expression changes in mouse uterine stromal cells during implantation.

    Chen L, Belton RJ and Nowak RA

    Department of Animal Sciences, University of Illinois, Urbana, IL 61801, USA.

    Implantation of mouse embryos is dependent on the proliferation and differentiation of uterine stromal cells in a process called decidualization. Decidualization both supports and limits the invasion of the implanting embryo and is regulated in part by the expression of matrix metalloproteinases (MMPs) and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). Molecules that alter the balance between MMP and TIMP expression could prevent implantation of the embryo. The membrane glycoprotein basigin (CD147/EMMPRIN), a known inducer of MMPs, is necessary for normal implantation in the mouse. The purpose of this study was to investigate the potential roles of basigin during implantation in the mouse. Using an in vitro stromal cell culture system, we found that recombinant human basigin protein (rBSG) increases MMP-3 and MMP-9 expression without altering TIMP-3 expression. Our results also showed rBSG induces expression of cytokines IL-1alpha/beta and leukocyte chemoattractants, CCL3, CCL20, CXCL2, and CXCL5. More importantly, rBSG significantly suppressed stromal cell decidualization as shown by the inhibition of alkaline phosphatase-2 expression and activity by rBSG. However, rBSG did not affect stromal cell proliferation. Taken together, our data indicate that basigin mediates gene expression changes in mouse uterine stromal cells and suggests that temporal and spatial regulation of basigin expression may be involved in the recruitment of leukocytes to the mouse uterus during early pregnancy.

    Funded by: NICHD NIH HHS: U54 HD40093

    Endocrinology 2009;150;2;966-76

  • Basal and stimulated lactate fluxes in primary cultures of astrocytes are differentially controlled by distinct proteins.

    Maekawa F, Minehira K, Kadomatsu K and Pellerin L

    Department of Physiology, University of Lausanne, Lausanne, Switzerland.

    Lactate release by astrocytes is postulated to be of importance for neuroenergetics but its regulation is poorly understood. Basigin, a chaperone protein for specific monocarboxylate transporters (MCTs), represents a putatively important regulatory element for lactate fluxes. Indeed, basigin knockdown by RNA interference in primary cultures of astrocytes partially reduced both proton-driven lactate influx and efflux. But more strikingly, enhancement of lactate efflux induced by glutamate was prevented while the effect of sodium azide was significantly reduced by treatment of cultured astrocytes with anti-basigin small interfering RNA. Enhancement of glucose utilization was unaffected under the same conditions. Basal lactate uptake and release were significantly reduced by MCT1 knockdown, even more so than with basigin knockdown, whereas glutamate-driven or sodium azide-induced enhancement of lactate release was not inhibited by either MCT1, 2, or 4 small interfering RNAs. In conclusion, MCT1 plays a pivotal role in the control of basal proton-driven lactate flux in astrocytes while basigin is only partly involved, most likely via its interaction with MCT1. In contrast, basigin appears to critically regulate the enhancement of lactate release caused by glutamate (or sodium azide) but via an effect on another unidentified transporter at least present in astrocytes in vitro.

    Journal of neurochemistry 2008;107;3;789-98

  • Evidence that CD147 modulation of beta-amyloid (Abeta) levels is mediated by extracellular degradation of secreted Abeta.

    Vetrivel KS, Zhang X, Meckler X, Cheng H, Lee S, Gong P, Lopes KO, Chen Y, Iwata N, Yin KJ, Lee JM, Parent AT, Saido TC, Li YM, Sisodia SS and Thinakaran G

    Department of Neurobiology and Neurology, The University of Chicago, Chicago, Illinois 60637, USA.

    Cerebral deposition of beta-amyloid (Abeta) peptides is a pathological hallmark of Alzheimer disease. Intramembranous proteolysis of amyloid precursor protein by a multiprotein gamma-secretase complex generates Abeta. Previously, it was reported that CD147, a glycoprotein that stimulates production of matrix metalloproteinases (MMPs), is a subunit of gamma-secretase and that the levels of secreted Abeta inversely correlate with CD147 expression. Here, we show that the levels and localization of CD147 in fibroblasts, as well as postnatal expression and distribution in brain, are distinct from those of integral gamma-secretase subunits. Notably, we show that although depletion of CD147 increased extracellular Abeta levels in intact cells, membranes isolated from CD147-depleted cells failed to elevate Abeta production in an in vitro gamma-secretase assay. Consistent with an extracellular source that modulates Abeta metabolism, synthetic Abeta was degraded more rapidly in the conditioned medium of cells overexpressing CD147. Moreover, modulation of CD147 expression had no effect on epsilon-site cleavage of amyloid precursor protein and Notch1 receptor. Collectively, our results demonstrate that CD147 modulates Abeta levels not by regulating gamma-secretase activity, but by stimulating extracellular degradation of Abeta. In view of the known function of CD147 in MMP production, we postulate that CD147 expression influences Abeta levels by an indirect mechanism involving MMPs that can degrade extracellular Abeta.

    Funded by: NIA NIH HHS: AG019070, AG021495, AG026660, R01 AG019070, R01 AG021495; NINDS NIH HHS: P01 NS032636, P01 NS032636-139001, R01 NS048283, R01 NS048283-03, R01 NS048283-04

    The Journal of biological chemistry 2008;283;28;19489-98

  • Characterization and regulation of monocarboxylate cotransporters Slc16a7 and Slc16a3 in preimplantation mouse embryos.

    Jansen S, Pantaleon M and Kaye PL

    School of Biomedical Sciences, University of Queensland, Brisbane 4072, Queensland, Australia.

    Concurrent with compaction, preimplantation mouse embryos switch from the high pyruvate consumption that prevailed during cleavage stages to glucose consumption against a constant background of pyruvate uptake. However, zygotes exposed to and subsequently deprived of glucose can form blastocysts by increasing pyruvate uptake. This metabolic switch requires cleavage-stage exposure to glucose and is one aspect of metabolic differentiation that normally occurs in vivo. Monocarboxylates, such as pyruvate and lactate, are transported across membranes via the SLC16 family of H(+)-monocarboxylate cotransporter (MCT) proteins. Thus, the increase in pyruvate uptake in embryos developing without glucose must involve changes in activity and localization of MCT. In mouse embryos, continued expression of Slc16a1 (MCT1) requires glucose supply. Messenger RNA for Slc17a7 (MCT2) and Slc16a3 (MCT4) has been detected in mouse preimplantation embryos; however, protein function, localization, and regulation of expression at the basis of these net pyruvate uptake changes remain unclear. The expression and localization of SLC16A7 and SLC16A3 have therefore been examined to clarify their respective roles in embryos derived from the reproductive tract and cultured under varied conditions. SLC16A3 appears localized to the plasma membrane until the morula stage and also maintains a nuclear distribution throughout preimplantation development. However, continued Slc16a3 mRNA expression is dependent on prior exposure to glucose. SLC16A7 localizes to apical cortical regions with punctate, vesicular expression throughout blastomeres, partially colocalizing in peroxisomes with peroxisomal catalase (CAT). In contrast to SLC16A3 and SLC16A1, SLC16A7 and CAT demonstrate upregulation in the absence of glucose. These striking differences between the two isoforms in expression localization and regulation suggest unique roles for each in monocarboxylate transport and pH regulation during preimplantation development, and implicate peroxisomal SLC16A7 as an important redox regulator in the absence of glucose.

    Funded by: NICHD NIH HHS: U01 HD044644

    Biology of reproduction 2008;79;1;84-92

  • Upregulation of EMMPRIN after permanent focal cerebral ischemia.

    Zhu W, Khachi S, Hao Q, Shen F, Young WL, Yang GY and Chen Y

    Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA.

    Elevated activities of matrix metalloproteinases (MMPs) following ischemic stroke have been shown to mediate ischemic injury as well as neurovascular remodeling. The extracellular MMP inducer (EMMPRIN) is a 58-kDa cell surface glycoprotein, which has been known to play a key regulatory role for MMP activities. The roles of EMMPRIN in stroke injury are not clearly understood. In this study, we investigated changes of EMMPRIN in a mouse model of permanent focal cerebral ischemia, and examined potential association between EMMPRIN and MMP-9 expression. Adult male CD-1 mice were subjected to permanent focal ischemia by intraluminal occlusion of the left middle cerebral artery (MCAO) under anesthesia. EMMPRIN expression was markedly upregulated in the peri-infarct area at 2-7 days after ischemia compared to the contralateral non-ischemic hemisphere by Western blot analysis. Immunofluorescent double staining demonstrated that EMMPRIN signals co-localized with vwF-positive endothelial cells and GFAP-positive peri-vascular astrocytes. In contrast, EMMPRIN signal did not co-localize with NeuN-positive neurons, or MPO-positive neutrophils. Dual fluorescent staining revealed that EMMPRIN co-localized with MMP-9. Our data also demonstrated that increased EMMPRIN expression correlated with increased MMP-9 levels in a temporal manner. In summary, we report for the first time that EMMPRIN expression was significantly increased in a mouse model of permanent focal cerebral ischemia. The spatial and temporal association between increased EMMPRIN expression and elevated MMP-9 levels suggest that EMMPRIN may modulate MMP-9 activity, and participate in neurovascular remodeling after ischemic stroke.

    Funded by: NINDS NIH HHS: P01 NS44145, R21 NS053943, R21 NS053943-01A1

    Neurochemistry international 2008;52;6;1086-91

  • CD147 regulates vascular endothelial growth factor-A expression, tumorigenicity, and chemosensitivity to curcumin in hepatocellular carcinoma.

    Jia L, Wang H, Qu S, Miao X and Zhang J

    Department of Biochemistry, Institute of Glycobiology, Dalian Medical University, Dalian, Liaoning Province, China.

    CD147, also named as extracelluar matrix metalloproteinase inducer (EMMPRIN), has been proved to be involved in several aspects of tumor progression. In addition to its ability to induce vascular endothelial growth factor (VEGF) production, it confers resistance to some chemotherapeutic drugs. To investigate the possible role of CD147 in the mouse hepatocarcinoma cell line Hepa1-6 with no metastatic potential in the lymph nodes, we used RNA interference (RNAi) approach to silence CD147 expression. The results showed that silencing of CD147 in Hepa1-6 cells significantly impeded the expression of VEGF-A at both mRNA and protein levels. The siRNA-treated cells exhibited significantly decreased growth ability when compared with control cells. Colony formation of CD147 deficient cells was dramatically inhibited in soft agar, and tumorigenicity was reduced in nude mice. Furthermore, the downregulation of CD147 expression also sensitized cells to be more sensitive to curcumin. These results suggested that CD147 might be a potential target for therapeutic antitumor drugs.

    IUBMB life 2008;60;1;57-63

  • HAb18G/CD147 functions in invasion and metastasis of hepatocellular carcinoma.

    Xu J, Xu HY, Zhang Q, Song F, Jiang JL, Yang XM, Mi L, Wen N, Tian R, Wang L, Yao H, Feng Q, Zhang Y, Xing JL, Zhu P and Chen ZN

    Cell Engineering Research Centre and Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, 17 West Changle Street, Xi'an 710032, China.

    CD147 molecule is reported to be correlated with the malignancy of some cancers; however, it remains unclear whether it is involved in the progression of hepatocellular carcinoma (HCC). Here, we investigated the function of HAb18G/CD147, a member of CD147 family, and its antibodies, HAb18 and LICARTIN, in HCC invasion and metastasis. We observed that HAb18G/CD147 gene silence in HCC cells significantly decreased the secretion of matrix metalloproteinase (MMP) and the invasive potential of HCC cells (P < 0.001). MMP silence in HCC cells also significantly suppressed the invasion of the cells when cocultured with fibroblasts; however, its inhibitory effect was significantly weaker than that of both HAb18G/CD147 silence in HCC cells and that of MMP silence in fibroblasts (P < 0.001). Blocking theHAb18G/CD147 molecule on HCC cells with HAb18 monoclonal antibody resulted in a similar suppressive effect on MMP secretion and cell invasion, but with no significant effects on the cell growth. (131)I-labeled HAb18 F(ab')(2) (LICARTIN), however, significantly inhibited the in vitro growth of HCC cells (P < 0.001). In an orthotopic model of HCC in nude mice, HAb18 and LICARTIN treatment effectively reduced the tumor growth and metastasis as well as the expression of three major factors in the HCC microenviroment (MMPs, vascular endothelial growth factor, and fibroblast surface protein) in the paracancer tissues. Overall, these results suggest that HAb18G/CD147 plays an important role in HCC invasion and metastasis mainly via modulating fibroblasts, as well as HCC cells themselves to disrupt the HCC microenviroment. LICARTIN can be used as a drug targeting to HAb18G/CD147 in antimetastasis and recurrence therapy of HCC.

    Molecular cancer research : MCR 2007;5;6;605-14

  • Expression of extracellular matrix metalloproteinase inducer and matrix metalloproteinases during mouse embryonic development.

    Chen L, Nakai M, Belton RJ and Nowak RA

    Department of Animal Sciences, University of Illinois, Urbana, Illinois 61801, USA.

    Mouse embryo implantation is a highly invasive and controlled process that involves remodeling and degradation of the extracellular matrix of the uterus. Matrix metalloproteinases (MMPs) are the main proteinases facilitating this process. Extracellular matrix metalloproteinase inducer (EMMPRIN) can stimulate the production of MMPs and is required for successful implantation in the mouse. The aims of the present study were to examine the expression profiles of mRNA and proteins for EMMPRIN and MMPs in the developing mouse embryo in vitro, and to study whether EMMPRIN protein induces the production of MMPs by mouse blastocysts. EMMPRIN mRNA, detected by RT-PCR, was present at all stages of embryo development from the one-cell to the blastocyst outgrowth. EMMPRIN protein, observed by confocal microscopy, was present on the cell surface at the same stages of development as was the mRNA. Of seven MMPs studied, murine collagenase-like A (Mcol-A), murine collagenase-like B (Mcol-B) and gelatinase A (MMP-2) mRNAs were detected only in blastocyst outgrowths by RT-PCR. Gelatinase B (MMP-9) mRNA was detected both in expanded blastocysts and blastocyst outgrowths. MMP-2 and -9 proteins were detected in the cytoplasm of outgrowing trophoblast cells. Collagenase-2 (MMP-8), collagenase-3 (MMP-13), or stromelysin-1 (MMP-3) mRNAs were not present at any stage of pre- or peri-implantation mouse embryo development. Quantitative RT-PCR analyses showed that recombinant EMMPRIN protein did not stimulate MMP-2 or -9 expression by mouse blastocyst outgrowths. These data suggest that EMMPRIN may regulate physiological functions other than MMP production by mouse embryos during implantation.

    Funded by: NICHD NIH HHS: U54 HD40093

    Reproduction (Cambridge, England) 2007;133;2;405-14

  • CD147 depletion down-regulates matrix metalloproteinase-11, vascular endothelial growth factor-A expression and the lymphatic metastasis potential of murine hepatocarcinoma Hca-F cells.

    Jia L, Cao J, Wei W, Wang S, Zuo Y and Zhang J

    Department of Biochemistry, Institute of Glycobiology, College of Laboratory Medicine, Dalian Medical University, Liaoning Province, China.

    Extracellular matrix metalloproteinase inducer (EMMPRIN, CD147), which is a plasma membrane glycoprotein enriched on the surface of many malignant tumors promotes adhesion, invasion and metastasis of tumor cells. In addition, tumor-associated CD147 also induces vascular endothelial growth factors (VEGFs) expression. To investigate the possible role of CD147 in the mouse hepatocarcinoma cell line Hca-F with highly metastatic potential in the lymph nodes, we used an RNA interference (RNAi) approach to silence CD147 expression. The results showed that CD147 depletion in Hca-F cells resulted in the significantly decreased expression of matrix metalloproteinase-11 (MMP-11), VEGF-A at both mRNA and protein levels. The reduced CD147 expression also attenuated the invasive, adhesive, metastatic ability of Hca-F cells to lymph nodes both in vitro and in vivo. Our current findings reveal that the tumor biological marker CD147 functionally mediates MMP-11, VEGF-A expression and tumor lymphatic metastasis.

    The international journal of biochemistry & cell biology 2007;39;11;2135-42

  • Matrix metalloproteinase induction in the tumor stroma does not depend on CD147 expression in murine B16 melanoma.

    Voigt H, Houben R, Schrama D, Hofmann UB, Vetter-Kauczok CS and Becker JC

    Department of Dermatology, Julius Maximilians University, Würzburg, Germany. Voigt_H@klinik.uni-wuerzburg.de

    Background: It was conclusively demonstrated that the cell surface glycoprotein CD147 on tumor cells mediates induction of matrix metalloproteinases (MMPs) by stromal cells in humans. However, for murine models such evidence remains elusive.

    To address the impact of CD147 on MMP expression in the murine B16 melanoma model, we consequently stably knocked down CD147 expression in two B16 sublines. The CD147 knockdown remained stable under in vivo conditions as confirmed by immunohistochemistry. However, no differences in MMP-2, MMP-9 and MT1-MMP expression by stromal and tumor cells were detectable in CD147+ and CD147- tumors. Since the tumor microenvironment is a complex system, involving several cell types, the extracellular matrix and plethora soluble factors, we subsequently studied the role of murine CD147 in vitro. Coculture of melanoma cells with different fibroblast cell lines demonstrated that neither CD147+ nor CD147- B16 tumor cells altered the expression of MMP-2 or MMP-9 by the fibroblasts, although we could confirm the susceptibility of these fibroblasts for MMP induction.

    Conclusions: At least for the murine B16 melanoma model, CD147 expression on tumor cells seems not to be crucial for MMP-2, MMP-9 and MT1-MMP induction on tumor-associated stromal cells.

    Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 2007;28;4;229-37

  • [Expression of various matrix metalloproteinases in mice with hyperoxia-induced acute lung injury].

    Zhang XF, Ding SF, Gao YM, Liang Y and Foda HD

    Department of Pulmonary Medicine, Beijing Anzhen Hospital, Beijing 100029, China. xfzh119@hotmail.com

    Objective: To investigate the role of matrix metalloproteinases (MMPs) and extracellular matrix metalloproteinase inducer (EMMPRIN) in the pathogenesis of acute lung injury induced by hyperoxia.

    Methods: Fifty four mice were exposed in sealed cages to >98% oxygen (for 24-72 hours), and another 18 mice to room air. The severity of lung injury was assessed, and the expression of mRNA and protein of MMP-2, MMP-9 and EMMPRIN in lung tissue, after exposure for 24, 48 and 72 hours of hyperoxia were studied by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry.

    Results: Hyperoxia caused acute lung injury; this was accompanied by increased expression of an upregulation of MMP-2, MMP-9 and EMMPRIN mRNA and protein in lung tissues.

    Conclusion: Hyperoxia causes acute lung injury in mice; increases in MMP-2, MMP-9 and EMMPRIN may play an important role in the development of hyperoxia induced lung injury in mice.

    Zhongguo wei zhong bing ji jiu yi xue = Chinese critical care medicine = Zhongguo weizhongbing jijiuyixue 2006;18;8;449-51

  • Tissue distribution of basigin and monocarboxylate transporter 1 in the adult male mouse: a study using the wild-type and basigin gene knockout mice.

    Nakai M, Chen L and Nowak RA

    Department of Animal Sciences, University of Illinois, Urbana, Illinois 61801, USA.

    Basigin (Bsg) is a transmembrane protein that is responsible for targeting of monocarboxylate transporters (MCTs) to the cell membrane. The present study was conducted to determine whether or not Bsg was required for the proper localization of MCT isoform 1 (MCT1) in a wide range of tissues in adult male mice. The tissue distributions of Bsg and MCT1 in wild-type (WT) mice, the tissue distribution of MCT1 in Bsg gene knockout (Bsg-KO) mice, and the protein and mRNA levels of MCT1 in both genotypes were studied. Immunohistochemistry demonstrated that Bsg colocalized with MCT1 in the cerebrum, retina, skeletal and cardiac muscle, duodenal epithelium, hepatic sinusoid, proximal uriniferous tubules, Leydig cells, and efferent ductule epithelium in WT mice. Bsg was absent but MCT1 was present in Sertoli cells, cauda epididymis, myoepithelial cells and duct of the mandibular gland, surface epithelium of the stomach and bronchioles. In Bsg-KO mice, with the exception of Leydig cells, MCT1 immunostaining was greatly reduced in intensity and its distribution was altered in tissues that expressed both Bsg and MCT1 in WT mice. Levels of the protein and mRNA for MCT1 in these tissues did not change significantly in Bsg-KO mice. On the other hand, immunostaining patterns in cells in which Bsg was absent but MCT1 was present in WT mice remained unchanged in Bsg-KO mice. These observations suggest that Bsg is required for the proper localization of MCT1 in a wide range of cells but not in every cell type.

    Funded by: NICHD NIH HHS: 1 U54 HD40093, U54 HD040093, U54 HD040093-08S20002

    The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology 2006;288;5;527-35

  • BGEM: an in situ hybridization database of gene expression in the embryonic and adult mouse nervous system.

    Magdaleno S, Jensen P, Brumwell CL, Seal A, Lehman K, Asbury A, Cheung T, Cornelius T, Batten DM, Eden C, Norland SM, Rice DS, Dosooye N, Shakya S, Mehta P and Curran T

    Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States.

    Funded by: NINDS NIH HHS: 5R37NS036558, N01-NS-0-2331, R37 NS036558

    PLoS biology 2006;4;4;e86

  • Deglycosylation of CD147 down-regulates Matrix Metalloproteinase-11 expression and the adhesive capability of murine hepatocarcinoma cell HcaF in vitro.

    Jia L, Zhou H, Wang S, Cao J, Wei W and Zhang J

    Department of Biochemistry, Institute of Glycobiology, Dalian Medical University, Dalian, China.

    CD147 is a plasma membrane glycoprotein, enriched on the surface of many malignant tumor cells. As a result of heterogeneous N-glycosylation, CD147 exists in both a highly glycosylated form, HG-CD147 ( approximately 40-60 kDa) and lowly glycosylated form, LG-CD147 ( approximately 32 kDa). This experiment investigated the possible role of CD147 glycosylation in the HcaF, HcaP and Hepa1-6 mouse hepatocarcinoma cell lines, which have high, low and no metastatic potential in the lymph nodes. Western blot analysis showed that the ratio of HG-CD147/LG-CD147 protein expression on HcaF and HcaP were much higher than that on Hepa1-6 cells. By treatment with tunicamycin (TM), an inhibitor of N-glycosylation, the expression level of HG-CD147 decreased and the LG-CD147 disappeared completely in HcaF cells. Meanwhile, Matrixmetallproteinase-11 (MMP-11) protein expression was down-regulated, and the adhesive capability of HcaF cells to endothelial cells in cryosection of mouse lymph nodes decreased. These results indicated that the glycosylation of CD147 plays a crucial role. It is HG-CD147 that may contribute more to tumor progress, invasion and metastasis into lymph node rather than LG-CD147. The results of this study are of biological and clinical importance.

    IUBMB life 2006;58;4;209-16

  • Caveolin-1 up-regulates CD147 glycosylation and the invasive capability of murine hepatocarcinoma cell lines.

    Jia L, Wang S, Zhou H, Cao J, Hu Y and Zhang J

    Department of Biochemistry, Institute of Glycobiology, Dalian Medical University, 465 Zhongshan Road, Dalian 116027, Liaoning Province, China.

    CD147 which is a regulator of matrix metalloproteinase (MMP) production on the surface of many malignant tumor cells, shows a highly specific association with caveolin-1 (Cav-1). As a result of heterogeneous N-glycosylation, CD147 exists in both highly glycosylated form, HG-CD147 ( approximately 40-60kDa) and lowly glycosylated form, LG-CD147 ( approximately 32kDa). This study investigated the possible role of Cav-1 in CD147 glycosylation in the HcaF, HcaP and Hepa1-6 mouse hepatocarcinoma cell lines, which have high, low and no metastatic potential in the lymph nodes, respectively, and in the normal mouse liver cell line IAR-20. Using an RNA interference (RNAi) strategy, we showed that the down-regulation of Cav-1 in Hca-F/RNAi cells could suppress the conversion of LG-CD147 to HG-CD147, down-regulate MMP-11 expression and decrease Hca-F/RNAi cell invasion. Conversely, a stable high expression of Cav-1 in Hepa1-6/Cav-1 cell could cause a specific increase of HG-CD147, up-regulate MMP-11 protein expression and enhance Hepa1-6/Cav-1 cell invasion. In conclusion, Cav-1 expression leads to an increased proportion of HG-CD147 relative to LG-CD147, increased production of MMP-11 and a higher invasive capability. Cav-1 is therefore proposed to act as both an oncogene and a tumor suppressor gene, and could represent a new potential target for gene therapy.

    The international journal of biochemistry & cell biology 2006;38;9;1584-93

  • Extracellular cyclophilins contribute to the regulation of inflammatory responses.

    Arora K, Gwinn WM, Bower MA, Watson A, Okwumabua I, MacDonald HR, Bukrinsky MI and Constant SL

    Department of Microbiology and Tropical Medicine, George Washington University, Washington, D.C. 20037, USA.

    The main regulators of leukocyte trafficking during inflammatory responses are chemokines. However, another class of recently identified chemotactic agents is extracellular cyclophilins, the proteins mostly known as receptors for the immunosuppressive drug, cyclosporine A. Cyclophilins can induce leukocyte chemotaxis in vitro and have been detected at elevated levels in inflamed tissues, suggesting that they might contribute to inflammatory responses. We recently identified CD147 as the main signaling receptor for cyclophilin A. In the current study we examined the contribution of cyclophilin-CD147 interactions to inflammatory responses in vivo using a mouse model of acute lung injury. Blocking cyclophilin-CD147 interactions by targeting CD147 (using anti-CD147 Ab) or cyclophilin (using nonimmunosuppressive cyclosporine A analog) reduced tissue neutrophilia by up to 50%, with a concurrent decrease in tissue pathology. These findings are the first to demonstrate the significant contribution of cyclophilins to inflammatory responses and provide a potentially novel approach for reducing inflammation-mediated diseases.

    Funded by: NIAID NIH HHS: AI-57527, R03 AI057527, R03 AI057527-02

    Journal of immunology (Baltimore, Md. : 1950) 2005;175;1;517-22

  • A genetic contamination in MHC-congenic mouse strains reveals a locus on chromosome 10 that determines autoimmunity and arthritis susceptibility.

    Nandakumar KS and Holmdahl R

    Medical Inflammation Research, Lund University, Lund, Sweden. nan@inflam.lu.se

    Among the arthritis-susceptible MHC (H-2)-congenic mouse strains, B10.RIII mice are highly susceptible to collagen-induced arthritis. Surprisingly, the B10.RIII strain was also more susceptible to the T cell independent model CAIA (collagen-antibody-induced arthritis). Through genome-wide genotyping, we found that the B10.RIII and B10.Q strains differed not only in chromosome 17 (MHC) but also in a region on chromosome 10, which contained a fragment from the MHC donor RIIIS/J. We isolated the chromosome 10 as well as the chromosome 17 segments on the B10.RIII and B10.Q backgrounds. Congenic mice containing the RIIIS/J-derived chromosome 10 segment showed significantly higher susceptibility and severity of arthritis with an enhanced autoimmune response to type II collagen. Furthermore, this chromosomal segment significantly promoted CAIA. Similarly, the RIIIS/J segment in chromosome 17 also promoted CAIA independently of other gene segments. These data show that other gene regions, apart from MHC class II, may explain effects both at the priming and effector level of arthritis observed in widely used MHC congenic strains. These new congenic fragments, on both chromosome 10 and 17, provide new mouse strains suitable for studies aiming at positional cloning of new genes associated with arthritis.

    European journal of immunology 2005;35;4;1275-82

  • Tagging genes with cassette-exchange sites.

    Cobellis G, Nicolaus G, Iovino M, Romito A, Marra E, Barbarisi M, Sardiello M, Di Giorgio FP, Iovino N, Zollo M, Ballabio A and Cortese R

    Telethon Institute of Genetics and Medicine, Via P. Castellino 111, 80131 Naples, Italy.

    In an effort to make transgenesis more flexible and reproducible, we developed a system based on novel 5' and 3' 'gene trap' vectors containing heterospecific Flp recognition target sites and the corresponding 'exchange' vectors allowing the insertion of any DNA sequence of interest into the trapped locus. Flp-recombinase-mediated cassette exchange was demonstrated to be highly efficient in our system, even in the absence of locus-specific selection. The feasibility of constructing a library of ES cell clones using our gene trap vectors was tested and a thousand insertion sites were characterized, following electroporation in ES cells, by RACE-PCR and sequencing. We validated the system in vivo for two trapped loci in transgenic mice and demonstrated that the reporter transgenes inserted into the trapped loci have an expression pattern identical to the endogenous genes. We believe that this system will facilitate in vivo studies of gene function and large-scale generation of mouse models of human diseases, caused by not only loss but also gain of function alleles.

    Funded by: Telethon: TGM03S01, TGM06S01

    Nucleic acids research 2005;33;4;e44

  • Accelerating effect of an MRL gene locus on the severity and onset of arthropathy in DBA/1 mice.

    Oishi H, Miyazaki T, Mizuki S, Kamogawa J, Lu LM, Tsubaki T, Arita N, Ono M, Yamamoto H and Nose M

    Ehime University School of Medicine, Onsen-gun, Japan.

    Objective: To analyze the influence of the genetic background of an arthritis-prone strain of mice, MRL, on the spontaneous development of arthropathy in DBA/1 mice, which histopathologically resembles enthesopathy in humans, and to clarify the strain-specific gene loci and their interactions that confer susceptibility to arthropathy.

    Methods: MRL, DBA/1, (MRL x DBA/1)F(1), and (MRL x DBA/1)F(2) intercross mice were prepared, and the severity and onset of arthropathy of the ankle joints in individual mice were quantified (0-3 and 0-5 scale, respectively). A genome-wide scan of 271 male F(2) intercross mice with polymorphic microsatellite markers was performed.

    Results: Only male DBA/1, (MRL x DBA/1)F(1), and (MRL x DBA/1)F(2) mice developed arthropathy. The macroscopic and histopathologic findings of arthropathy in the F(2) mice were similar to those in the parental DBA/1 mice, but the onset was significantly earlier. In the quantitative trait locus analysis of male F(2) mice, 1 susceptibility locus for both the severity and early onset of the disease in the region of an MRL allele, Amd1, was located at marker D10Mit259 (map position 40.0 cM), which was common to 1 of the sialadenitis susceptibility loci in MRL mice, Asm1. Another susceptibility locus for the severity and early onset of arthropathy in the region of a DBA allele, Amd2, was located at D3Mit46 (29.5 cM). These loci manifested an additive effect on the development of arthropathy.

    Conclusion: Arthropathy in DBA/1 mice is under the control of an allelic combination of gene loci, one of which is common to the locus for sialadenitis in MRL/MpJ-lpr/lpr mice.

    Arthritis and rheumatism 2005;52;3;959-66

  • HAb18G/CD147 enhances the secretion of matrix metalloproteinases (MMP) via cGMP/NO-sensitive capacitative calcium entry (CCE) and accordingly attenuates adhesion ability of fibroblasts.

    Huang Y, Jiang J, Dou K and Chen Z

    Cell Engineering Research Centre & Department of Cell Biology, The Fourth Military Medical University, Xi'an 710032, PR China.

    The present study examined the effect of hepatoma-associated antigen HAb18G (homologous to CD147) expression on the NO/cGMP-regulated Ca2+ mobilization to induce matrix metalloproteinases (MMP) production and attenuate adhesion ability of mouse fibroblast NIH/3T3 cells. HAb18G/CD147 cDNA was transfected into fibroblast 3T3 cells to obtain a cell line stably expressing HAb18G/CD147, t3T3, as demonstrated by immunofluorescence staining and flow cytometry assays. 8-Bromo-cGMP inhibited the thapsigargin-induced Ca2+ entry in 3T3 cells, whereas an inhibitor of protein kinase G, KT5823 (1 microM), led to an increase in Ca2+ entry. Expression of HAb18G/CD147 in t3T3 cells decreased the inhibitory response to cGMP. A similar effect on the Ca2+ entry was observed in 3T3 cells in response to an NO donor, (+/-)-S-nitroso-N-acetylpenicillamine (SNAP). The inhibitory effect of SNAP on the thapsigargin-induced Ca2+ entry was also reduced in HAb18G/CD147-expressing t3T3 cells, indicating a role for HAb18G/CD 147 in NO/cGMP-regulated Ca2+ entry. Results of gelatin zymography assays showed that addition of extracellular Ca2+ induced MMP (MMP-2, MMP-9) release and activation in a dose-dependent manner, and expression of HAb18G/CD147 enhanced the secretion of MMP-2 and MMP-9 in 3T3 cells. 8-Bromo-cGMP and SNAP reduced the production of MMP in 3T3 cells but not in t3T3 with HAb18G/CD147 expression. RT-PCR experiments substantiated that the expression of MMP-2 and MMP-9 mRNA in HAb18G/CD 147-expressing t3T3 cell was significantly greater than that in 3T3 cells. Experiments investigating adhesion potentials demonstrated that HAb18G/CD147-expressing t3T3 cells pretreated with Ca2+ attached to Matrigel-coated culture plates significantly less efficiently than 3T3 cells. The proportion of attached cells could be increased by treatment with 8-bromo-cGMP and SNAP in 3T3 cells, but not in t3T3. These results suggest that HAb18G/CD147 attenuates adhesion potentials in fibroblasts by enhancing the secretion of MMP through NO/cGMP-sensitive capacitative Ca2+ entry.

    European journal of cell biology 2005;84;1;59-73

  • Libraries enriched for alternatively spliced exons reveal splicing patterns in melanocytes and melanomas.

    Watahiki A, Waki K, Hayatsu N, Shiraki T, Kondo S, Nakamura M, Sasaki D, Arakawa T, Kawai J, Harbers M, Hayashizaki Y and Carninci P

    Genome Science Laboratory, RIKEN, Wako main campus, 2-1 Hirosawa, Wako, Saitama, 351-0198 Japan.

    It is becoming increasingly clear that alternative splicing enables the complex development and homeostasis of higher organisms. To gain a better understanding of how splicing contributes to regulatory pathways, we have developed an alternative splicing library approach for the identification of alternatively spliced exons and their flanking regions by alternative splicing sequence enriched tags sequencing. Here, we have applied our approach to mouse melan-c melanocyte and B16-F10Y melanoma cell lines, in which 5,401 genes were found to be alternatively spliced. These genes include those encoding important regulatory factors such as cyclin D2, Ilk, MAPK12, MAPK14, RAB4, melastatin 1 and previously unidentified splicing events for 436 genes. Real-time PCR further identified cell line-specific exons for Tmc6, Abi1, Sorbs1, Ndel1 and Snx16. Thus, the ASL approach proved effective in identifying splicing events, which suggest that alternative splicing is important in melanoma development.

    Nature methods 2004;1;3;233-9

  • Effects of flanking genes on the phenotypes of mice deficient in basigin/CD147.

    Chen S, Kadomatsu K, Kondo M, Toyama Y, Toshimori K, Ueno S, Miyake Y and Muramatsu T

    Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.

    The induction of null mutations by means of homologous recombination is a powerful technique for clarifying the biological activities of target genes. However, the problems of the genetic background and flanking genes should be borne in mind. Here we employed a breeding strategy to compare three lines of mice deficient in the basigin (Bsg)/CD147 gene. The first line was F2 from F1 hybrid offspring of the 129/SV chimera and C57BL/6J. The second one was from a C57BL/6J congenic line. Both lines showed high embryonic lethality, sterility, and blindness. The third one was 'reverse F2' from 'reverse F1' hybrid offspring of the C57BL/6J congenic line and 129/SV. Surprisingly, this line showed a normal birth rate, while sterility and blindness persisted. Our results clearly separate the effects of the induced null mutation from those of flanking genes and the genetic background, and provide a useful means of investigating the biological functions of Bsg.

    Biochemical and biophysical research communications 2004;324;1;147-53

  • The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

    Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Morrin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J and MGC Project Team

    The National Institutes of Health's Mammalian Gene Collection (MGC) project was designed to generate and sequence a publicly accessible cDNA resource containing a complete open reading frame (ORF) for every human and mouse gene. The project initially used a random strategy to select clones from a large number of cDNA libraries from diverse tissues. Candidate clones were chosen based on 5'-EST sequences, and then fully sequenced to high accuracy and analyzed by algorithms developed for this project. Currently, more than 11,000 human and 10,000 mouse genes are represented in MGC by at least one clone with a full ORF. The random selection approach is now reaching a saturation point, and a transition to protocols targeted at the missing transcripts is now required to complete the mouse and human collections. Comparison of the sequence of the MGC clones to reference genome sequences reveals that most cDNA clones are of very high sequence quality, although it is likely that some cDNAs may carry missense variants as a consequence of experimental artifact, such as PCR, cloning, or reverse transcriptase errors. Recently, a rat cDNA component was added to the project, and ongoing frog (Xenopus) and zebrafish (Danio) cDNA projects were expanded to take advantage of the high-throughput MGC pipeline.

    Funded by: PHS HHS: N01-C0-12400

    Genome research 2004;14;10B;2121-7

  • Basigin expression and regulation in mouse ovary during the sexual maturation and development of corpus luteum.

    Chang H, Ni H, Ma XH, Xu LB, Kadomatsu K, Muramatsu T and Yang ZM

    College of Life Sciences, Northeast Agricultural University, Harbin 150030, China.

    Basigin is a highly glycosylated transmembrane protein belonging to the immunoglobulin superfamily. Basigin-deficient male mice are azoospermic. The majority of basigin null embryos die around the time of implantation. However, basigin expression and regulation in mouse ovary is still unknown. The aim of this study was to investigate basigin expression in mouse ovary during sexual maturation, gonadotropin treatment, and luteal development by in situ hybridization and immunohistochemistry. Both basigin mRNA and immunostaining were not detected in the granulosa cells of preantral follicles until day 20 after birth. On day 30 after birth, basigin immunostaining dropped to a basal level, while basigin mRNA was still at a high level. Basigin expression was strongly induced by equine chorionic gonadotropin (eCG) treatment at 4 and 8 hr post-eCG injection. Both basigin immunostaining and mRNA signals were strongly observed in the corpus luteum on days 2 and 3 post-hCG injection. However, no basigin expression was detected from days 6 to 15 post-hCG injection. In conclusion, our data suggest that basigin may play a role during the mouse follicle development and corpus luteum formation.

    Molecular reproduction and development 2004;68;2;135-41

  • Developmental analyses of 5A11/Basigin, 5A11/Basigin-2 and their putative binding partner MCT1 in the mouse eye.

    Clamp MF, Ochrietor JD, Moroz TP and Linser PJ

    The Whitney Laboratory, University of Florida, 9505 Ocean Shore Boulevard, St Augustine, FL 32080, USA.

    Recent reports by this laboratory and others have demonstrated an association between 5A11/Basigin, a member of the immunoglobulin gene superfamily, and monocarboxylate transporter-1 (MCT1), a lactose transporter. Indeed, it was determined in the 5A11/Basigin null mouse retina that MCT1 does not properly integrate into the cell membranes of Müller cells (MCs) or the retinal-pigmented epithelium, where the two are colocalized. The purpose of this study was to elucidate the association of 5A11/Basigin and MCT1 in the developing mouse retina. Immunocytochemical localization and real-time RT-PCR were used to evaluate the expression and localization of 5A11/Basigin and MCT1 at embryonic days 12, 15, and 18, as well as post-natal days 1, 7, 14, and 21. Expression of both proteins progressed from a more generalized distribution throughout the undifferentiated neural retina to specific staining of retina-pigmented epithilia, the MCs, photoreceptor cells and the ciliary apparatus. Although these two membrane glycoproteins were often colocalized, distinct differences in the location and magnitude of their expression over time was observed. These findings suggest that although 5A11/Basigin and MCT1 can associate within the cell membrane, their expression is not always associated and colocalized.

    Funded by: NEI NIH HHS: F32EY13918

    Experimental eye research 2004;78;4;777-89

  • Bioinformatics and cellular signaling.

    Papin J and Subramaniam S

    Department of Bioengineering, University of California at San Diego, La Jolla, CA 92037, USA.

    The understanding of cellular function requires an integrated analysis of context-specific, spatiotemporal data from diverse sources. Recent advances in describing the genomic and proteomic 'parts list' of the cell and deciphering the interrelationship of these parts are described, including genome-wide location analysis, standards for microarray data analysis, and two-hybrid and mass spectrometry approaches. This information is being collected and curated in databases such as the Alliance for Cellular Signaling (AfCS) Molecule Pages, which will serve as vital tools for the reconstruction and analysis of cellular signaling networks.

    Current opinion in biotechnology 2004;15;1;78-81

  • Wnk1 kinase deficiency lowers blood pressure in mice: a gene-trap screen to identify potential targets for therapeutic intervention.

    Zambrowicz BP, Abuin A, Ramirez-Solis R, Richter LJ, Piggott J, BeltrandelRio H, Buxton EC, Edwards J, Finch RA, Friddle CJ, Gupta A, Hansen G, Hu Y, Huang W, Jaing C, Key BW, Kipp P, Kohlhauff B, Ma ZQ, Markesich D, Payne R, Potter DG, Qian N, Shaw J, Schrick J, Shi ZZ, Sparks MJ, Van Sligtenhorst I, Vogel P, Walke W, Xu N, Zhu Q, Person C and Sands AT

    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381, USA. brian@lexgen.com

    The availability of both the mouse and human genome sequences allows for the systematic discovery of human gene function through the use of the mouse as a model system. To accelerate the genetic determination of gene function, we have developed a sequence-tagged gene-trap library of >270,000 mouse embryonic stem cell clones representing mutations in approximately 60% of mammalian genes. Through the generation and phenotypic analysis of knockout mice from this resource, we are undertaking a functional screen to identify genes regulating physiological parameters such as blood pressure. As part of this screen, mice deficient for the Wnk1 kinase gene were generated and analyzed. Genetic studies in humans have shown that large intronic deletions in WNK1 lead to its overexpression and are responsible for pseudohypoaldosteronism type II, an autosomal dominant disorder characterized by hypertension, increased renal salt reabsorption, and impaired K+ and H+ excretion. Consistent with the human genetic studies, Wnk1 heterozygous mice displayed a significant decrease in blood pressure. Mice homozygous for the Wnk1 mutation died during embryonic development before day 13 of gestation. These results demonstrate that Wnk1 is a regulator of blood pressure critical for development and illustrate the utility of a functional screen driven by a sequence-based mutagenesis approach.

    Proceedings of the National Academy of Sciences of the United States of America 2003;100;24;14109-14

  • A novel form of the membrane protein CD147 that contains an extra Ig-like domain and interacts homophilically.

    Hanna SM, Kirk P, Holt OJ, Puklavec MJ, Brown MH and Barclay AN

    Sir William Dunn School of Pathology, University of Oxford, South Parks Road, OX1 3RE, United Kingdom. melanie_hanna@yahoo.ca

    Background: CD147 is a broadly distributed integral membrane glycoprotein with two Ig-like domains implicated in a wide range of functions. It is associated at the cell surface with the monocarboxylate transporters MCT1 and 4 but interactions of the extracellular region have not been characterised.

    Results: We report the characterisation of a form of CD147 with an additional membrane-distal Ig-like domain. In contrast to the two domain form, this three domain form of CD147 interacts homophilically. Surface plasmon resonance analysis using recombinant proteins showed that the interaction was of low affinity (KD approximately 40 microM) and this is typical of many interactions between membrane proteins. cDNA for the 3 domain form are rare but have been identified in human and mouse retina.

    Conclusion: The finding that the three domain form of CD147 has an extracellular ligand, that is it interacts homophilically, suggests this interaction may be important in aligning lactate transporters in the retina where lactate is an important metabolite.

    BMC biochemistry 2003;4;17

  • Retina-specific expression of 5A11/Basigin-2, a member of the immunoglobulin gene superfamily.

    Ochrietor JD, Moroz TP, van Ekeris L, Clamp MF, Jefferson SC, deCarvalho AC, Fadool JM, Wistow G, Muramatsu T and Linser PJ

    Whitney Laboratory of the University of Florida, St. Augustine, Florida 32080, USA. jdo@whitney.ufl.edu

    Purpose: 5A11/Basigin has recently been identified as a critical glycoprotein for full maturity and function of the mouse retina. However, the biological function of 5A11/Basigin has yet to be determined. Previous reports indicate the presence of multiple 5A11/Basigin polypeptides within the retina. Therefore, in an effort to determine the function of 5A11/Basigin, the molecular diversity of its expression was evaluated.

    Methods: Northern blot and immunoblot techniques were used to evaluate the number of forms of 5A11/Basigin in the mouse retina. cDNA cloning, using a mouse retina library or RT-PCR from rat, chicken, zebrafish, and human retina, was performed to determine the sequence of 5A11/Basigin transcripts. A peptide was generated, based on the deduced amino acid sequence, for subsequent antibody production. Localization of 5A11/Basigin expression was evaluated by immunoblot, immunohistochemistry, and real-time RT-PCR.

    Results: Two 5A11/Basigin transcripts of approximately 1.5 kb and approximately 1.8 kb, which correspond to glycosylated proteins of approximately 45 and approximately 55 kDa, respectively, were identified in mouse retina. The shorter form was previously cloned. However, the longer form, a splice variant of mouse 5A11/Basigin, is a member of the immunoglobulin gene superfamily and has been named 5A11/Basigin-2. Homologous transcripts were also cloned from rat, chicken, zebrafish, and human retina. 5A11/Basigin-2 expression was limited to the retina, specifically to photoreceptor cells, where it appeared to be most concentrated in the inner segments.

    Conclusions: The specific and limited expression of 5A11/Basigin-2 explicitly within photoreceptor cells implies that this glycoprotein plays a fundamental role within the retina. However, its role remains to be determined.

    Funded by: NEI NIH HHS: EY13020, F32EY13918

    Investigative ophthalmology & visual science 2003;44;9;4086-96

  • Basigin (CD147): a multifunctional transmembrane protein involved in reproduction, neural function, inflammation and tumor invasion.

    Muramatsu T and Miyauchi T

    Department of Biochemistry, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan. tmurama@med.nagoya-u.ac.jp

    Basigin (Bsg) is a transmembrane glycoprotein with two immunoglobulin-like domains, and forms a family with embigin and neuroplastin. In these proteins a conserved glutamic acid is present in the middle for the transmembrane domain. Bsg is also called CD147 and EMMPRIN, and the symbol for the human basigin gene is BSG. BSG is located in chromosome 19 band p13. 3. Knockout mice deficient in the Bsg gene are sterile and show various neurological abnormalities. Bsg-deficient embryos are also difficult to implant. Bsg has been found to participate in the cell-surface orientation of monocarboxylic acid transporters (MCTs) to the plasma membrane. Dysfunction of the retina in Bsg-deficient mice is ascribed to the failure of plasma membrane integration of MCTs in the tissue. Bsg is also involved in inflammatory processes and is proposed to be a receptor of cyclophilin A; it is also likely to participate in HIV infection. Bsg in tumor cells triggers the production or release of matrix metalloproteinases in the surrounding mesenchymal cells and tumor cells, thereby contributing to tumor invasion. Furthermore, the association of Bsg with integrins might be important in signaling through Bsg.

    Histology and histopathology 2003;18;3;981-7

  • Differential expression of tissue inhibitor of metalloproteinases type 1 (TIMP-1) during mouse gonad development.

    Guyot R, Magre S, Leduque P and Le Magueresse-Battistoni B

    Inserm U329, Hopital Debrousse, Lyon, France.

    In mammals, the gene Sry initiates signaling pathways triggering the differentiation of a testis from a sexually indifferent gonad. Assuming that these morphogenetic events may alter the proteolytic balance, the expression of matrix metalloproteinases (MMPs) and inhibitors (TIMPs) was investigated in gonads from 11.5 days postcoitum (dpc) onward, when testicular organogenesis occurs. Whereas selective MMPs and TIMPs (1-3) were detected in undifferentiated gonads (11.5 dpc) and in neonatal testes, a single TIMP (TIMP-1) was expressed in a sexually dimorphic manner from 12.5 dpc onward (i.e., after overt male gonad differentiation), demonstrated by using a semiquantitative reverse transcriptase-polymerase chain reaction and a Western blot analysis. To gain insight into the role of TIMP-1, the expression of gelatinases (mRNA levels and enzyme activity) was monitored. However, no sex differences could be evidenced, indicating that TIMP-1 was not inhibiting this class of MMPs during testis organogenesis. Apart from being an inhibitor of MMPs, TIMP-1 is known to display growth promoting activities. Of interest, testicular TIMP-1 (but not TIMP-2) levels were further enhanced up to 2 weeks of age, consistent with a role in the early postnatal testicular growth. We, therefore, established an organotypic culture system in which seminiferous cords may differentiate de novo and grow, depending on culture conditions. In that system and mimicking the in vivo situation, TIMP-1 immunolocalized strongly within the male gonadal territory and weakly in female gonads, in which no organization was evident. Experiments are now under way to determine to what extent TIMP-1 is a morphogenic gene involved in seminiferous cord formation and development.

    Developmental dynamics : an official publication of the American Association of Anatomists 2003;227;3;357-66

  • Increased basigin in bleomycin-induced lung injury.

    Betsuyaku T, Kadomatsu K, Griffin GL, Muramatsu T and Senior RM

    Department of Medicine and Cell Biology, Washington University School of Medicine, Barnes-Jewish Hospital, St. Louis, Missouri, USA. bytomoko@med.hokudai.ac.jp

    Basigin is expressed in many tissues during development, including lung. It is also found on tumor cells and in wounds where it is thought to stimulate adjacent fibroblasts to produce matrix metalloproteinases. To investigate whether basigin might be expressed in fibro-inflammatory lung processes, we generated bleomycin-induced lung injury in mice. At 14 d after intratracheal bleomycin, we found basigin prominently in areas of fibrosis, alveolar macrophages, and bronchiolar epithelium, whereas it was only weakly present in bronchiolar epithelium in untreated mice. Western blots of radioimmunoprecipitation assay RIPA-insoluble fractions of bleomycin-treated lungs showed increased basigin compared with RIPA-insoluble fractions of lung from untreated mice. By quantitative reverse transcriptase-polymerase chain reaction, lung basigin mRNA was significantly increased 14 d after bleomycin, and by in situ hybridization, basigin mRNA was prominent in bronchiolar epithelium. Western blots of bronchoalveolar lavage fluid (BALF) showed various forms of basigin after bleomycin that were not present in BALF from untreated lung. These results demonstrate that bleomycin-induced lung injury is associated with increased basigin expression in bronchiolar epithelium, deposition of basigin in fibrotic sites, and increased basigin in BALF. Accordingly, basigin may play a role in diffuse alveolar injury.

    Funded by: NHLBI NIH HHS: HL-29594, HL-47328

    American journal of respiratory cell and molecular biology 2003;28;5;600-6

  • Loss of MCT1, MCT3, and MCT4 expression in the retinal pigment epithelium and neural retina of the 5A11/basigin-null mouse.

    Philp NJ, Ochrietor JD, Rudoy C, Muramatsu T and Linser PJ

    Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. nancy.philip@mail.tju.edu

    Purpose: The neural retina expresses multiple monocarboxylate transporters (MCTs) that are likely to play a key role in the metabolism of the outer retina. Recently, it was reported that targeting of MCT1 and -4 to the plasma membrane requires association with 5A11/basigin (CD147). In the present study, the hypothesis that reduced amplitudes in the electroretinograms in the 5A11/basigin null mouse (Bsg(-/-)) may be linked to altered expression of MCTs was studied.

    Methods: The expression and subcellular distribution of MCTs in Bsg(-/-) mice was analyzed by immunofluorescence microscopy with isoform-specific antibodies. Protein expression was analyzed by Western blot analysis, and mRNA expression was examined with RT-PCR.

    Results: Immunofluorescence labeling of tissue sections from the Bsg(-/-) mice revealed a dramatic reduction in labeling with MCT antibodies. There was a loss of MCT1 labeling in the apical membrane of the RPE and in the neural retina. MCT3, which is expressed in the basolateral membrane of the RPE wild-type mouse, was expressed at very low levels in both the apical and basolateral membranes of the Bsg(-/-) mouse. There was no change in expression or distribution of the glucose transporter (GLUT)-1 in the RPE and retina of the Bsg(-/-) mouse. Western blot analysis of detergent-soluble lysates prepared from wild-type and Bsg(-/-) eyes confirmed that the levels of MCT1, MCT3, and MCT4 protein were severely reduced in Bsg(-/-) mice. RT-PCR analyses of mRNA levels from wild-type and Bsg(-/-) mice demonstrated that the MCT1 transcript was expressed at normal levels in Bsg(-/-) mice.

    Conclusions: In Bsg(-/-) mice, there is a severe reduction in accumulation of the MCT1 and -3 proteins in the RPE and a concomitant reduction in MCT1 and -4 in the neural retina supporting a role for 5A11/basigin in the targeting of these transporters to the plasma membrane. Decreased expression of MCT1 and -4 on the surfaces of Müller and photoreceptor cells may compromise energy metabolism in the outer retina, leading to abnormal photoreceptor cell function and degeneration.

    Funded by: NEI NIH HHS: EY12042, F32EY13918

    Investigative ophthalmology & visual science 2003;44;3;1305-11

  • The immunoglobulin-superfamily molecule basigin is a binding protein for oligomannosidic carbohydrates: an anti-idiotypic approach.

    Heller M, von der Ohe M, Kleene R, Mohajeri MH and Schachner M

    Department of Neurobiology, Swiss Federal Institute of Technology, Zürich, Switzerland.

    Recognition molecules that carry carbohydrate structures regulate cell interactions during development and play important roles in synaptic plasticity and regeneration in the adult. Glycans appear to be involved in these interactions. We have searched for binding proteins for oligomannosidic structures using the L3 antibody directed against high mannose-type glycans in an anti-idiotypic approach. A selected monoclonal anti-idiotype antibody was used for affinity chromatography and identified basigin as a binding protein from mouse brain detergent lysates. Basigin was found to bind to high mannose-carrying cell recognition molecules, such as myelin-associated glycoprotein, L1, the beta2-subunit of Na+/K+-ATPase and an oligomannosidic neoglycolipid. Furthermore, basigin was involved in outgrowth of astrocytic processes in vitro. A striking homology between the first immunoglobulin (Ig)-like domain of basigin and the fourth Ig-like domain of NCAM, previously shown to bind to oligomannosidic glycans, and the lectin domain of the mannose receptor confirms that basigin is an oligomannose binding lectin. To our knowledge this is the first report that anti-idiotypic antibodies can be used to identify binding partners for carbohydrates.

    Journal of neurochemistry 2003;84;3;557-65

  • Identification of a monogenic locus (jams1) causing juvenile audiogenic seizures in mice.

    Misawa H, Sherr EH, Lee DJ, Chetkovich DM, Tan A, Schreiner CE and Bredt DS

    Department of Physiology, University of California at San Francisco, School of Medicine, San Francisco, California 94143-0444, USA.

    Epilepsy is a debilitating disease with a strong genetic component. Positional cloning has identified a few genes for rare monogenic epilepsy syndromes; however, the genetics of common human epilepsies are too complex to be analyzed easily by current techniques. Mouse models of epilepsy can further this analysis by eliminating genetic background heterogeneity and enabling the production of sufficient numbers of offspring. Here, we report that Black Swiss mice have a heretofore unrecognized specific susceptibility to audiogenic seizures. These seizures are characterized by wild running, loss of righting reflex, and tonic flexion and extension, and are followed by a postictal period. The susceptibility to these seizures is developmentally regulated, peaking at 21 d of age and nearly disappearing by adulthood. Interestingly, both the susceptibility to seizures and their developmental regulation appear unrelated to hearing thresholds in the Black Swiss strain and backcrossed progeny. Genetic mapping and linkage analysis of hybrid mice localize the seizure gene, jams1 (juvenile audiogenic monogenic seizures), to a 1.6 +/- 0.5 centimorgan (cM) region on mouse chromosome 10, delimited by the gene basigin (Bsg) and marker D10Mit140. Interestingly, the majority of the critical region is syntenic to a region on human chromosome 19p13.3 implicated in a familial form of juvenile febrile convulsions. Cloning the gene for audiogenic seizures in these mice may provide important insight into the fundamental mechanisms for developmentally regulated human epilepsy syndromes.

    Funded by: NIDCD NIH HHS: R01 DC002260, R01 DC002260-08

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2002;22;23;10088-93

  • Basigin expression and hormonal regulation in mouse uterus during the peri-implantation period.

    Xiao LJ, Chang H, Ding NZ, Ni H, Kadomatsu K and Yang ZM

    College of Life Science, Northeast Agricultural University, Harbin, China.

    Basigin, a transmembrane glycoprotein belonging to the immunoglobulin superfamily, has been shown to be essential for fertilization and implantation. The aim of this study was to determine the expression and hormonal regulation of basigin gene in mouse uterus during the peri-implantation period. Basigin immunostaining and mRNA were strongly localized in luminal and glandular epithelium on day 1 of pregnancy and gradually decreased to a basal level from day 2-4 of pregnancy. Basigin mRNA expression in the sub-luminal stroma was first detected on day 3 of pregnancy and increased on day 4 of pregnancy. On day 5 of pregnancy, the expression of basigin protein and mRNA was only detected in the implanting embryos, and the luminal epithelium and sub-luminal stroma surrounding the embryos. A similar expression pattern of basigin was also induced in the delayed-implantation uterus which was activated by estrogen injection. On day 6-8 of pregnancy, although a basal level of basigin protein was detected in the secondary decidual zone, basigin mRNA expression was strongly seen in this location. Basigin mRNA was also highly expressed in the decidualized cells under artificial decidualization. Estrogen significantly stimulated basigin expression in the ovariectomized mouse uterus. A high level of basigin immunostaining and mRNA was also seen in proestrus and estrus uteri. These results suggest that basigin expression is closely related to mouse implantation and up-regulated by estrogen.

    Molecular reproduction and development 2002;63;1;47-54

  • A role for CD147 in thymic development.

    Renno T, Wilson A, Dunkel C, Coste I, Maisnier-Patin K, Benoit de Coignac A, Aubry JP, Lees RK, Bonnefoy JY, MacDonald HR and Gauchat JF

    Centre d'Immunologie Pierre Fabre, 5 Avenue Napoleon III, Saint-Julien en Genevois, 74160 France.

    We have previously identified a mAb that binds to a molecule expressed preferentially on the surface of cycling thymocytes. In this study the molecule recognized by this mAb has been identified in the mouse as CD147 (basigin) by expression cloning. We show that CD147 expression correlates with cycling of immature thymocytes even in the absence of TCRbeta selection and that ligation of this molecule on immature fetal thymocytes inhibits their further development into mature T cells.

    Journal of immunology (Baltimore, Md. : 1950) 2002;168;10;4946-50

  • Genetic expression of monocarboxylate transporters during human and murine oocyte maturation and early embryonic development.

    Hérubel F, El Mouatassim S, Guérin P, Frydman R and Ménézo Y

    Laboratoire Marcel Mérieux, Lyon, France.

    During the early preimplantationes of human embryos, pyruvate and lactate, but not glucose, are the preferred energy substrates. Transport of these monocarboxylates is mediated, in mammalian cells, by a family of transporters, designated as monocarboxylate transporters (MCTs). Human and mouse genetic expression of MCT members 1, 2, 3, 4 and basigin, a chaperone protein of MCT1 and MCT4, was qualitatively analysed using the reverse transcription nested polymerase chain reaction (RT-nested PCR) in immature oocytes (germinal vesicle stage; GV), in non-fertilised metaphase II (MII) oocytes and in embryos from 2-cell stage to blastocysts. Transcripts encoding for MCT1 and MCT2 were present, under a polyadenylated form, in the majority of the human and mouse oocytes and early embryos. MCT3 transcripts were not detected in either human or mouse. MCT4 mRNA was not detected in human oocytes and embryos, but was present in mouse oocytes and embryos. This fact could imply differences in lactate transport and regulation of intracellular pH between human and murine early embryos. Basigin transcripts were present in mouse and human MII oocytes and preimplantation embryos, but were not detected at GV stage. However, using 3' end-specific primers in the RT reaction instead of Oligo(dT)12-18 primers, transcripts encoding for this protein were then detected at GV stage in both species. This result suggests that a regulated polyadenylation process occurs during oocyte maturation for these transcripts. Thus, basigin mRNA can be considered as a marker of oocyte cytoplasmic maturation in human and mouse species.

    Zygote (Cambridge, England) 2002;10;2;175-81

  • Behaviour of a sperm surface transmembrane glycoprotein basigin during epididymal maturation and its role in fertilization in mice.

    Saxena DK, Oh-Oka T, Kadomatsu K, Muramatsu T and Toshimori K

    Department of Anatomy and Reproductive Cell Biology, Miyazaki Medical College, Kihara 5200, Kiyotake, Miyazaki 889-1692, Japan.

    Basigin (bsg) is a transmembrane glycoprotein belonging to an immunoglobulin superfamily and is localized on the surface of the sperm tail. The behaviour of bsg during epididymal maturation and its role in fertilization were examined using an anti-bsg antibody. Spermatozoa from caput, corpus and cauda epididymides were immunostained by indirect immunofluorescence (IIF). Immunostaining revealed that bsg is localized on the principal piece of caput spermatozoa and the molecule was found on the middle piece during transit in the corpus and cauda epididymides. Concomitantly, the molecular mass of bsg was reduced from 37 kDa (testis) to 26 kDa (cauda epididymidis). IVF experiments were designed to assess the effect of anti-bsg antibody on the fertilization events. Anti-bsg antibody significantly inhibited primary binding to the cumulus-invested oocytes with intact zonae pellucidae in a dose-dependent manner. Consequently, the fertilization rate of cumulus-invested oocytes with intact zonae pellucidae was also inhibited. The bsg molecule was also detected on the head of live capacitated spermatozoa by IIF under IVF conditions. These findings indicate that testicular bsg is a glycosylated protein that undergoes molecular processing and deglycosylation during its transit in the epididymis. The bsg molecule that was detected on the sperm head after capacitation may facilitate the primary binding or might be involved in distinct events required for primary binding of spermatozoa to the zona pellucida during capacitation and sperm-cumulus interaction.

    Reproduction (Cambridge, England) 2002;123;3;435-44

  • Gene-expression profile of collagen-induced arthritis.

    Ibrahim SM, Koczan D and Thiesen HJ

    Institute of Immunology, University of Rostock, Schillingallee 70, Rostock, 18055, Germany. saleh.ibrahim@med.uni-rostock.de

    To provide a global analysis of genes involved in the inflammatory process in joints of DBA/1J mice suffering from collagen induced arthritis (CIA) we used oligonucleotide microarrays representing approximately 11,000 genes to determine the gene expression profile of the inflamed paws at peak of disease, and compared them to normal tissue. Peak of disease was determined from clinical evaluation of disease and histopathology of joints. Of the 11,000 genes assayed, 223 showed differential expression of four fold or more (187 upregulated and 36 downregulated). Ninety-five of the genes observed had well-characterized full length sequences in databases, and 128 were unknown (Ests). Inflammation resulted in a profile of increased gene expression of matrix metalloproteinases, immune-related, extra-cellular matrix and cell adhesion molecules, as well as molecules involved in cell division and transcription; differential regulation of molecules involved in signal transduction, protein synthesis and metabolism. Of the 55 genes with known chromosomal locations nine mapped to previously identified QTL, contributing to susceptibility or severity of CIA, i.e. MHC class I, II, Basigin, FAP, Cathepsin K, CD 53, RAF1, glucagon, and retinal taurine transporter. The profile of gene expression supports current theoretical models of disease progression and might open new perspectives for both diagnosis and treatment of arthritis.

    Journal of autoimmunity 2002;18;2;159-67

  • Inactivation of the Basigin gene impairs normal retinal development and maturation.

    Ochrietor JD, Moroz TP, Clamp MF, Timmers AM, Muramatsu T and Linser PJ

    The Whitney Laboratory of the University of Florida, 9505 Ocean Shore Boulevard, St., Augustine, FL 32080, USA.

    5A11/Basigin is an immunoglobulin-like glycoprotein expressed on the surface of Müller cells, the apical and basal surfaces of the retinal pigmented epithelium, and photoreceptor cell bodies and their inner segments. Disruption of the 5A11/Basigin gene in the mouse results in photoreceptor degeneration and a corresponding decrease in electroretinogram amplitudes in mature mice. The purpose of this study was to examine the electrophysiology of the 5A11/Basigin null mouse retina at earlier ages than previously examined. Although the architecture of the 5A11/Basigin null mouse retina appears normal, the ERG amplitudes are severely depressed at eye opening, indicating failure in retinal maturation.

    Funded by: NEI NIH HHS: T32 EY07132-08

    Vision research 2002;42;4;447-53

  • Retinal degeneration following failed photoreceptor maturation in 5A11/basigin null mice.

    Ochrietor JD, Moroz TM, Kadomatsu K, Muramatsu T and Linser PJ

    The Whitney Laboratory of the University of Florida, St. Augustine, FL 32080, USA.

    5A11/Basigin is a member of the immunoglobulin gene superfamily which plays an important role in cell-cell interactions in the developing neural retina. These studies were initiated to investigate the distribution of 5A11/Basigin within the mouse retina, as well as the cytoarchitectural and biochemical effects on the retina after the inactivation of the 5A11/Basigin gene in a mouse strain. Immunocytochemical analyses indicated that mouse 5A11/Basigin is located on the surface of Müller cells, the apical and basal surfaces of the retinal pigmented epithelium, and blood vessels. Lower expression levels were found on photoreceptor cell bodies and a portion of the inner segments. Inactivation of the 5A11/Basigin gene in mice resulted in the failure of photoreceptor cells to fully mature. This failed development eventually lead to the degeneration, death and removal of most of the photoreceptors several months after birth. Biochemical analyses indicated that expression of Müller cell specific proteins, including glutamine synthetase and carbonic anhydrase-II, was not effected; however, opsin protein expression never achieved normal adult levels in the 5A11/Basigin null mice. Also, 5A11/Basigin null retinas were considered 'reactive' based on elevated glial fibrillary acidic protein expression. The results presented here suggest that 5A11/Basigin expression on Müller cells and/or the retinal pigmented epithelium is necessary for photoreceptor outer segment biochemical development and structural maintenance. However, the exact role that 5A11/Basigin plays during retinal development remains to be determined.

    Experimental eye research 2001;72;4;467-77

  • Comparative maps of human 19p13.3 and mouse chromosome 10 allow identification of sequences at evolutionary breakpoints.

    Puttagunta R, Gordon LA, Meyer GE, Kapfhamer D, Lamerdin JE, Kantheti P, Portman KM, Chung WK, Jenne DE, Olsen AS and Burmeister M

    Mental Health Research Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.

    A cosmid/bacterial artificial chromosome (BAC) contiguous (contig) map of human chromosome (HSA) 19p13.3 has been constructed, and over 50 genes have been localized to the contig. Genes and anonymous ESTs from approximately 4000 kb of human 19p13.3 were placed on the central mouse chromosome 10 map by genetic mapping and pulsed-field gel electrophoresis (PFGE) analysis. A region of approximately 2500 kb of HSA 19p13.3 is collinear to mouse chromosome (MMU) 10. In contrast, the adjacent approximately 1200 kb are inverted. Two genes are located in a 50-kb region after the inversion on MMU 10, followed by a region of homology to mouse chromosome 17. The synteny breakpoint and one of the inversion breakpoints has been localized to sequenced regions in human <5 kb in size. Both breakpoints are rich in simple tandem repeats, including (TCTG)n, (CT)n, and (GTCTCT)n, suggesting that simple repeat sequences may be involved in chromosome breaks during evolution. The overall size of the region in mouse is smaller, although no large regions are missing. Comparing the physical maps to the genetic maps showed that in contrast to the higher-than-average rate of genetic recombination in gene-rich telomeric region on HSA 19p13.3, the average rate of recombination is lower than expected in the homologous mouse region. This might indicate that a hot spot of recombination may have been lost in mouse or gained in human during evolution, or that the position of sequences along the chromosome (telomeric compared to the middle of a chromosome) is important for recombination rates.

    Funded by: NINDS NIH HHS: NS32130, R01 NS032130

    Genome research 2000;10;9;1369-80

  • Retinal dysfunction in basigin deficiency.

    Hori K, Katayama N, Kachi S, Kondo M, Kadomatsu K, Usukura J, Muramatsu T, Mori S and Miyake Y

    Department of Ophthalmology, Nagoya University School of Medicine, Tsuruma-cho, Showa-ku, Japan.

    Purpose: To examine the retina of basigin (Bsg) knockout mice by electrophysiological and histologic methods and thereby to determine the possible function of Bsg in phototransduction and retinal development.

    Methods: Scotopic and photopic electroretinograms (ERGs) were recorded from 11 wild-type, 12 heterozygous, and 8 homozygous Bsg gene knockout mice of different ages. The retinas were also examined by histologic and immunolabeling methods.

    Results: Bsg knockout mice of 5 to 41 weeks of age showed a decrease in the amplitude of all components of both the photopic and scotopic ERGs. In contrast, the fundus and the fluorescein fundus angiography and morphology of the retina at the light microscopic level appeared to be normal until 8 weeks of age in Bsg knockout mice. Thereafter, the length of outer segment and outer nuclear layers decreased with increasing age. Immunohistochemical analysis localized Bsg protein in a variety of cells in the retina, especially in the pigment epithelium, the upper outer plexiform layer and the inner segments of photoreceptor cells.

    Conclusions: The results demonstrated that both rod and cone function were severely affected from an early age by the targeted disruption of the Bsg gene. In spite of abnormal ERGs, the photoreceptor cells maintained normal morphology up to 8 weeks. Thereafter, the photoreceptor cells degenerated gradually and were almost ablated by 41 weeks.

    Investigative ophthalmology & visual science 2000;41;10;3128-33

  • Genome-wide expression profiling of mid-gestation placenta and embryo using a 15,000 mouse developmental cDNA microarray.

    Tanaka TS, Jaradat SA, Lim MK, Kargul GJ, Wang X, Grahovac MJ, Pantano S, Sano Y, Piao Y, Nagaraja R, Doi H, Wood WH, Becker KG and Ko MS

    Laboratory of Genetics and DNA Array Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224-6820, USA.

    cDNA microarray technology has been increasingly used to monitor global gene expression patterns in various tissues and cell types. However, applications to mammalian development have been hampered by the lack of appropriate cDNA collections, particularly for early developmental stages. To overcome this problem, a PCR-based cDNA library construction method was used to derive 52,374 expressed sequence tags from pre- and peri-implantation embryos, embryonic day (E) 12.5 female gonad/mesonephros, and newborn ovary. From these cDNA collections, a microarray representing 15,264 unique genes (78% novel and 22% known) was assembled. In initial applications, the divergence of placental and embryonic gene expression profiles was assessed. At stage E12.5 of development, based on triplicate experiments, 720 genes (6.5%) displayed statistically significant differences in expression between placenta and embryo. Among 289 more highly expressed in placenta, 61 placenta-specific genes encoded, for example, a novel prolactin-like protein. The number of genes highly expressed (and frequently specific) for placenta has thereby been increased 5-fold over the total previously reported, illustrating the potential of the microarrays for tissue-specific gene discovery and analysis of mammalian developmental programs.

    Proceedings of the National Academy of Sciences of the United States of America 2000;97;16;9127-32

  • Histological characterization of defective spermatogenesis in mice lacking the basigin gene.

    Toyama Y, Maekawa M, Kadomatsu K, Miyauchi T, Muramatsu T and Yuasa S

    Department of Anatomy and Developmental Biology, School of Medicine, Chiba University, Japan. toyama@med.m.chiba-u.ac.jp

    Basigin is a transmembrane protein belonging to the immunoglobulin superfamily. In the light of the fact that knockout mice lacking the basigin gene (Bsg) are azoospermic, the phenotype in the male reproductive system was extensively examined in this study. Spermatogenesis in Bsg (-/-) mice was found to be disrupted, and arrested at the metaphase of the first meiotic division. A few germ cells differentiated into young spermatids, but they were exfoliated. The lumens of the male reproductive system were filled with round degenerated cells. Using the TUNEL method and electron microscopy, some of the degenerated cells in the testis and epididymal head were shown to be apoptotic. Crystalloids of fine tubules and unusual ectoplasmic specializations were also observed in the Sertoli cells of Bsg (-/-) mice. These specializations displayed unusual 'circular' structures. Furthermore, unusual ectoplasmic specializations covering the spermatocytes rather than the mature spermatids were found. These structures were formed as a result of the lack of mature spermatids in the Bsg (-/-) testis. Results from analyses of azoospermia in the Bsg (-/-) mice suggest that basigin, through the interactions between germ cells and Sertoli cells, is an essential factor in the growth and/or survival of spermatids.

    Anatomia, histologia, embryologia 1999;28;3;205-13

  • Embigin/basigin subgroup of the immunoglobulin superfamily: different modes of expression during mouse embryogenesis and correlated expression with carbohydrate antigenic markers.

    Fan QW, Kadomatsu K, Uchimura K and Muramatsu T

    Department of Biochemistry, Nagoya University School of Medicine, Japan.

    Embigin and basigin are highly glycosylated transmembrane glycoproteins with two immunoglobulin domains and form a subgroup in the immunoglobulin superfamily. Previous studies have demonstrated the functional significance of these molecules. In the present study, in situ hybridization analysis of their expression was performed during mouse embryogenesis. Embigin was strongly expressed in the endoderm during early postimplantation embryogenesis, and in the somite stage in the gut and visceral endoderm. Embryonic ectoderm and its derivative tissues weakly to moderately expressed this molecule. From day 10 to 15 of gestation, no embigin signal was detected. Basigin was more broadly expressed. During the organogenesis period, basigin was expressed in various epithelial tissues, brain ventricles, the spinal cord and dorsal root ganglion. The modes of expression of these two proteins throughout the egg cylinder stage correlated with the expression of the carbohydrate markers that they carry; embigin with Dolichos biflorus agglutinin binding sites and basigin with LeX antigen and more closely with fucosyltransferase IV, which forms the antigenic epitope. These findings imply that proteins with specific carbohydrate epitopes play roles in early postimpantation embryogenesis.

    Development, growth & differentiation 1998;40;3;277-86

  • Female sterility in mice lacking the basigin gene, which encodes a transmembrane glycoprotein belonging to the immunoglobulin superfamily.

    Kuno N, Kadomatsu K, Fan QW, Hagihara M, Senda T, Mizutani S and Muramatsu T

    Department of Biochemistry, Nagoya University School of Medicine, Japan.

    Basigin (Bsg) is a transmembrane glycoprotein belonging to the immunoglobulin superfamily. Bsg knock-out mice exhibit infertility of both sexes. Based on limited results, defective implantation has been considered to be the cause of the female infertility. We demonstrate here that disruption of the Bsg gene produces the failure of female reproductive processes including not only implantation but also fertilization. Bsg mRNA expression in cumulus cells and basolateral localization of the Bsg protein in the endometrial epithelium further support the importance of Bsg in these processes.

    FEBS letters 1998;425;2;191-4

  • A null mutation in basigin, an immunoglobulin superfamily member, indicates its important roles in peri-implantation development and spermatogenesis.

    Igakura T, Kadomatsu K, Kaname T, Muramatsu H, Fan QW, Miyauchi T, Toyama Y, Kuno N, Yuasa S, Takahashi M, Senda T, Taguchi O, Yamamura K, Arimura K and Muramatsu T

    Department of Biochemistry, Nagoya University School of Medicine, Japan.

    Basigin is a highly glycosylated transmembrane protein with two immunoglobulin-like domains. We generated mutant mice lacking the basigin gene (Bsg) by gene targeting. Bsg (-/-) embryos developed normally during preimplantation stages. However, the majority of Bsg (-/-) embryos died around the time of implantation. At this time, basigin mRNA was strongly expressed in the trophectoderm, embryo proper, and uterine endometrium of Bsg (+/+) mice. These results suggest that basigin is involved in intercellular recognition during implantation. Embryos which survived the critical period yielded Bsg (-/-) mutant mice. Half of the mutant mice died before 1 month after birth, due to interstitial pneumonia. The surviving adult mutant mice were small and sterile. Spermatogenesis was arrested in the mutant mice. Most of the spermatocytes in the Bsg (-/-) mouse were arrested and degenerated at the metaphase of the first meiosis, and only a small number differentiated to step 1 spermatids. In the female mutants, the ovaries and genital tract were morphologically normal, and the defect was probably in the capability of implantation of the uterus. In conclusion, basigin is an important cell-surface molecule involved in early embryogenesis and reproduction.

    Developmental biology 1998;194;2;152-65

  • Expression of basigin, a member of the immunoglobulin superfamily, in the mouse central nervous system.

    Fan QW, Yuasa S, Kuno N, Senda T, Kobayashi M, Muramatsu T and Kadomatsu K

    Department of Biochemistry, Nagoya University School of Medicine, Japan.

    Basigin (Bsg) is a transmembrane glycoprotein belonging to the immunoglobulin superfamily. Chicken Bsg (HT7/neurothelin/ 5A11) is expressed in neuroblasts, but disappears from neurons after a specific stage of cytodifferentiation, and becomes restrictedly expressed in the capillary endothelium in the adult brain. We show herein by means of in situ hybridization that Bsg mRNA was expressed in neuroblasts in 13.5 day old mouse embryos. In the adult mouse, Bsg was differentially expressed in subregions of the brain. Strong Bsg expression was detected in the limbic system, including the olfactory system, hippocampal formation, septal area, amygdala, thalamic anterior nuclei, hypothalamus, mesencephalic tegmentum, entorhinal cortex, and cingulate gyrus. Bsg was also intensely expressed in the retinal neuronal layers, the Vth layer of the cerebral neocortex, Purkinje cells of the cerebellum, several nuclei of the brain stem, and the gray matter of the spinal cord. Although in situ hybridization showed a weak signal in the brain capillary endothelium, protein expression of Bsg was strong enough to be detected by immunohistochemistry. Northern blot analysis confirmed the strong expression of Bsg in the central nervous system. Taking into account that Bsg knockout mice exhibit abnormalities in behavior, but a normal blood-brain barrier function, the present findings suggest that Bsg functions actively in neuronal interactions in the central nervous system.

    Neuroscience research 1998;30;1;53-63

  • Abnormalities of sensory and memory functions in mice lacking Bsg gene.

    Naruhashi K, Kadomatsu K, Igakura T, Fan QW, Kuno N, Muramatsu H, Miyauchi T, Hasegawa T, Itoh A, Muramatsu T and Nabeshima T

    Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University School of Medicine, Showa-ku, Japan.

    Basigin is a highly glycosylated transmembrane protein belonging to the immunoglobulin superfamily. We used mutant mice lacking the basigin gene (Bsg) to investigate its involvement in learning and memory. Mutations were generated by the gene targeting method. Various kinds of learning and memory tasks were performed in mutant, hetero and wild type mice. The mutant mice showed worse performance than the wild and hetero mice in the Y-maze task, which assesses short-term memory, and in the water finding task, which examines latent learning, without any motor dysfunction. Moreover, the mutant mice showed less acclimation in the habituation task compared with the wild-type mice. The mutant mice were also more sensitive to electric foot-shock. These findings are consistent with the expression profile of basigin in the central nervous system. Thus, basigin may play an important role in learning and memory as well as in the sensory functions.

    Biochemical and biophysical research communications 1997;236;3;733-7

  • The neurological mouse mutations jittery and hesitant are allelic and map to the region of mouse chromosome 10 homologous to 19p13.3.

    Kapfhamer D, Sweet HO, Sufalko D, Warren S, Johnson KR and Burmeister M

    Mental Health Research Institute, University of Michigan, Ann Arbor 48109-0720, USA.

    Jittery (ji) is a recessive mouse mutation on Chromosome 10 characterized by progressive ataxic gait, dystonic movements, spontaneus seizures, and death by dehydration/starvation before fertility. Recently, a viable neurological recessive mutation, hesitant, was discovered. It is characterized by hesitant, unco-ordinated movements, exaggerated stepping of the hind limbs, and reduced fertility in males. In a complementation test and by genetic mapping we have shown here that hesitant and jittery are allelic. Using several large intersubspecific backcrosses and intercrosses we have genetically mapped ji near the marker Amh and microsatellite markers D10Mit7, D10Mit21, and D10Mit23. The linked region of mouse Chromosome 10 is homologous to human 19p13.3, to which several human ataxia loci have recently been mapped. By excluding genes that map to human 21q22.3 (Pfkl) and 12q23 (Nfyb), we conclude that jittery is not likely to be a genetic mouse model for human Unverricht-Lundborg progressive myoclonus epilepsy (EPM1) on 21q22.3 nor for spinocerebellar ataxia II (SCA2) on 12q22-q24. The closely linked markers presented here will facilitate positional cloning of the ji gene.

    Funded by: NINDS NIH HHS: NS32130

    Genomics 1996;35;3;533-8

  • Roles of basigin, a member of the immunoglobulin superfamily, in behavior as to an irritating odor, lymphocyte response, and blood-brain barrier.

    Igakura T, Kadomatsu K, Taguchi O, Muramatsu H, Kaname T, Miyauchi T, Yamamura K, Arimura K and Muramatsu T

    Department of Biochemistry, Nagoya University School of Medicine, Japan.

    Basigin is a transmembrane glycoprotein belonging to the immunoglobulin superfamily. Using the knockout mouse lacking the basigin gene (Bsg), we analyzed the function of basigin in adult mice lacking the gene [Bsg (-1-)]. Although histochemical studies on the localization of basigin (also called HT7 and neurothelin) strongly indicated that it is involved in the function of the blood-brain barrier, basigin knockout mice showed only a little difference, if any, to wild-type mice in the function of the blood brain-barrier. The mitogenic response of lymphocytes upon mixed lymphocyte reaction was greater in Bsg (-1-) mice. Finally, Bsg (-1-) mice repeatedly visited filter paper impregnated with acetic acid or isozine, indicating an abnormality in either reception of the odor or behavior as to it.

    Biochemical and biophysical research communications 1996;224;1;33-6

  • Cloning of the rabbit homologue of mouse 'basigin' and rat 'OX-47': kidney cell type-specific expression, and regulation in collecting duct cells.

    Schuster VL, Lu R, Kanai N, Bao Y, Rosenberg S, Prié D, Ronco P and Jennings ML

    Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

    Monoclonal antibody '4D4' was generated against a gel-purified 43-50 kDa fraction of rabbit erythrocyte (RBC) ghosts. Immunoblots of rabbit RBCs, skeletal muscle, and kidney, and of a rabbit cortical collecting duct cell line (RC.SV3) yielded broad bands of 30-70 kDa that migrated at approximately 31 kDa after deglycosylation. In kidney sections, 4D4 labeled the basal plasma membranes of the proximal tubule, medullary thick ascending limb of Henle, cortical, medullary, and papillary collecting ducts, and papillary surface epithelium, as well as the lateral membranes of alpha and beta-type intercalated cells. Antibody 4D4 was used to clone a full-length kidney cDNA, which predicted a 31 kDa immunoglobulin-like glycoprotein with high homology to mouse 'gp42' or 'basigin', human 'M6' or 'EMMPRIN', rat 'OX-47' or 'CE-9', and avian 'neurothelin', 'HT7', or '5A11'. When heterologously expressed in HeLa cells, glycosylated immunoreactive protein was expressed at the plasma membrane. In the case of the endogenous protein in RC.SV3 cells, interferon-gamma and A23187 decreased, and fetal calf serum increased, steady-state mRNA levels. Thus, this molecule exhibits a high degree of cell type-specific expression in the kidney and undergoes regulation by cytokines and serum in kidney epithelial cells.

    Funded by: NIDDK NIH HHS: R01 DK049688, R01-DK38095, R01-DK49688; NIGMS NIH HHS: R01-GM2681

    Biochimica et biophysica acta 1996;1311;1;13-9

  • Structure of the mouse basigin gene, a unique member of the immunoglobulin superfamily.

    Miyauchi T, Jimma F, Igakura T, Yu S, Ozawa M and Muramatsu T

    Japan Immunoreasearch Laboratories, Gunma.

    Basigin is a membrane glycoprotein belonging to the immunoglobulin superfamily. The mouse basigin gene was isolated from a genomic DNA library of the BALB/c mouse, and the structure of the gene and its flanking region (11.8 kb) was completely determined. The mouse basigin gene consists of seven exons and six introns spanning 7.5 kb. The distance between the first and second exons is 5.1 kb. The first immunoglobulin-like domain of the basigin molecule is encoded by the second and third exons, and the second immunoglobulin-like domain by the fourth and fifth exons. The fifth exon encodes not only the C proximal portion of the second immunoglobulin-like domain, but also the transmembrane domain and a small portion of the cytoplasmic domain. Thus, the organization of the basigin gene is unique. The 5' upstream sequence of the basigin gene contains no TATA box or CAAT box, but has a CpG-rich island. The BALB/c genomic sequence of all seven exons is consistent with the cDNA sequences of the 129/SV and Swiss mice except several minor substitutions in the 3'-terminal sequence of the 3'-noncoding region. No protein polymorphism has so far been found in basigin of different mouse strains.

    Journal of biochemistry 1995;118;4;717-24

  • Genetic map of the region around grizzled (gr) and mocha (mh) on mouse chromosome 10, homologous to human 19p13.3.

    Kapfhamer D and Burmeister M

    Mental Health Research Institute, University of Michigan, Ann Arbor 48109-0720.

    Grizzled (gr) is a recessive mouse mutation resulting in a gray coat color and reduced perinatal viability. Mocha (mh) is one of several recessive mouse mutants characterized by platelet storage pool disorder, pigment abnormalities, reduced fertility, kidney function deficiencies, and, in some mutants, inner ear and natural killer cell deficiencies. Murine platelet storage pool deficient mutants may be models for Chediak-Higashi and Hermansky-Pudlak syndromes in humans. The genes for gr and mh are very closely linked to each other (0 +/- 1.2 cM). However, their relative position with respect to molecular markers was previously unknown. Thus, genetic mapping of the gr locus will also yield information about the mh location. To map these two genes genetically, we have performed an intersubspecific backcross of grizzled mice with Mus musculus castaneus. In 539 progeny tested, we found no recombination between the gr gene, the gene for anti-Muellerian hormone (Amh), and the microsatellite markers D10Mit7, D10Mit21, and D10Mit23. One recombination event for each of the flanking markers Basigin (Bsg) and D10Mit22 was identified. These closely linked markers should provide entry points for positional cloning of the gr and mh genes. The region linked to grizzled is homologous to a gene-rich region on human Chromosome 19p13.3.

    Funded by: NINDS NIH HHS: NS32130-01

    Genomics 1994;23;3;635-42

  • Organization of the mouse GP42/Basigin gene: a member of the Ig superfamily.

    Cheng Y, Li X, Kamholz J and Burns FR

    Neurology Department, University of Pennsylvania, Philadelphia 19104.

    We have mapped and sequenced the GP42/Basigin gene isolated from a Balb/C mouse genomic library. The genomic organization and upstream, putative regulatory, regions of this gene have not been previously reported. Our data show that exon 5 of the GP42/Basigin gene encodes the carboxy proximal half of the second Ig-like domain, the highly conserved transmembrane region and a portion of the cytoplasmic tail. This inclusion of Ig-like and other functional domains in a single exon is unusual. Splice junction analysis indicates that two reported alternate GP42/Basigin cDNA isoforms are likely due to cloning artifacts. In addition, we find that GP42/Basigin is polymorphic in mice. Our data also support the proposal that the transmembrane domain and portions of the cytoplasmic region of GP42/Basigin have been evolutionarily conserved.

    Biochimica et biophysica acta 1994;1217;3;307-11

  • Expression of the HT7 gene in blood-brain barrier.

    Unger CM, Seulberger H, Breier G, Albrecht U, Achen MG and Risau W

    Max-Planck-Institut für Psychiatrie, Martinsried, Germany.

    Advances in experimental medicine and biology 1993;331;211-5

  • Chromosomal localization of two cell surface-associated molecules of potential importance in development: midkine (Mdk) and basigin (Bsg).

    Simon-Chazottes D, Matsubara S, Miyauchi T, Muramatsu T and Guénet JL

    Unité de Génétique des Mammifères de l'Institut Pasteur, Paris, France.

    Mammalian genome : official journal of the International Mammalian Genome Society 1992;2;4;269-71

  • Polymorphisms revealed by PCR with single, short-sized, arbitrary primers are reliable markers for mouse and rat gene mapping.

    Serikawa T, Montagutelli X, Simon-Chazottes D and Guénet JL

    Unité de Génétique des Mammifères de l'Institut Pasteur, Paris, France.

    Ten single, arbitrarily designed oligodeoxynucleotide primers, with 50-70% (G+C) content, were used to amplify by polymerase chain reaction (PCR) sequences with DNA templates from several mouse species (Mus spretus, Mus musculus musculus, and Mus musculus domesticus), as well as DNA from the laboratory rat (Rattus norvegicus). Eight of these ten primers, used either individually or associated in pairs, generated a total of 13 polymorphic products which were used as genetic markers. All of these polymorphic sequences but one were mapped to a particular mouse chromosome, by use of DNA panels prepared either from interspecific backcross progeny of the type (C57BL/6 x Mus spretus)F1 x C57BL/6 or DNA samples prepared from two sets of recombinant inbred (RI) strains (AKXL and BXD). Six rat-specific DNA segments were also assigned to a particular chromosome with DNA panels prepared from 18 rat/mouse somatic cell hybrids segregating rat chromosomes. From these experiments we conclude that, under precisely standardized PCR conditions, the DNA molecules amplified with these arbitrarily designed primers are useful and reliable markers for genetic mapping in both mouse and rat.

    Mammalian genome : official journal of the International Mammalian Genome Society 1992;3;2;65-72

  • The basigin group of the immunoglobulin superfamily: complete conservation of a segment in and around transmembrane domains of human and mouse basigin and chicken HT7 antigen.

    Miyauchi T, Masuzawa Y and Muramatsu T

    Japan Immunoresearch Laboratories, Gunma.

    Basigin belongs to the immunoglobulin superfamily and may be related to the primordial form of the superfamily. Human basigin cDNA was isolated and sequenced, and the predicted protein structure was compared with that of mouse basigin and two related molecules, embigin and the chicken blood-brain barrier antigen HT7. Between human and mouse basigin, 58% of the amino acids were identical and 80% of the changes were conservative. A stretch of 29 amino acid residues in the transmembrane and cytoplasmic domains was conserved not only in human and mouse basigin but also in HT7 antigen. The conserved structure may be required for interaction with a membranous protein. In addition, the relationship of basigin with other members of the immunoglobulin superfamily has been evaluated.

    Journal of biochemistry 1991;110;5;770-4

  • Basigin, a new member of the immunoglobulin superfamily: genes in different mammalian species, glycosylation changes in the molecule from adult organs and possible variation in the N-terminal sequences.

    Kanekura T, Miyauchi T, Tashiro M and Muramatsu T

    Department of Dermatology, Faculty of Medicine, Kagoshima University, Japan.

    Basigin is a new member of the immunoglobulin superfamily with homology to both the immunoglobulin V domain and major histocompatibility complex class II antigen beta-chain. Southern blot analysis indicated that the basigin gene was present as a single copy or as a few copies per mouse genome. Although a homologous gene was detected in the hamster and human, Southern and Northern blotting experiments indicated considerable species specificity in the basigin structure. The molecular weight of N-glycanase-treated basigin from embryonal carcinoma cells was about 32,000 and was close to the value of basigin polypeptide inferred from the cDNA sequence; the result confirmed the open reading frame of basigin. Upon Western blotting, large amounts of basigin were detected in the mouse kidney as a glycoprotein bound to Ricinus communis agglutinin (RCA)-I and as a glycoprotein bound to concanavalin A; the molecular weight of the former was 38,000-43,000, and of the latter was 30,000. Basigin of the molecular weight of 48,000 was detected in RCA-I-binding glycoproteins of the liver, small intestine and spleen. Thus, different forms of basigin can be produced by different modes of glycosylation. Another source of heterogeneity of basigin may be differences in N-terminal sequences, since cDNA clones with different 5' coding sequences were identified.

    Cell structure and function 1991;16;1;23-30

  • Basigin, a new, broadly distributed member of the immunoglobulin superfamily, has strong homology with both the immunoglobulin V domain and the beta-chain of major histocompatibility complex class II antigen.

    Miyauchi T, Kanekura T, Yamaoka A, Ozawa M, Miyazawa S and Muramatsu T

    Japan Immunoresearch Laboratories, Gumma.

    Lotus tetragonolobus agglutinin (LTA) binds preferentially to early embryonic cells in the mouse. The affinity-purified antibody raised against LTA receptors from embryonal carcinoma cells were used to screen a lambda gt11 expression library of F9 embryonal carcinoma cells, resulting in detection of a cDNA clone specifying a new glycoprotein termed "basigin." The glycoprotein has been suggested to be a transmembrane one, and was found to be a new member of the immunoglobulin (Ig) superfamily. The molecular weight of basigin was largely in the range between 43,000 and 66,000, while that of the peptide portion with a putative signal sequence was inferred to be about 30,000. Significant levels of basigin mRNA were detected not only in embryonal carcinoma cells, but also in mouse embryos at 9-15 days of gestation and in various organs of the adult mouse. The Ig-like domain of basigin is unique, since it has strong homology to both the beta-chain of major histocompatibility class II antigen and the Ig V domain. The number of amino acids between the two conserved cysteine residues is intermediate between those of the Ig V and C domains. Therefore, basigin is an interesting protein in connection with the molecular evolution of the superfamily.

    Journal of biochemistry 1990;107;2;316-23

  • Cloning of cDNA for a novel mouse membrane glycoprotein (gp42): shared identity to histocompatibility antigens, immunoglobulins and neural-cell adhesion molecules.

    Altruda F, Cervella P, Gaeta ML, Daniele A, Giancotti F, Tarone G, Stefanuto G and Silengo L

    Dipartimento di Genetica, Biologia e Chimica Medica, Università di Torino, Italy.

    A full-length clone encoding a murine membrane glycoprotein, gp42, was selected from a mouse fibroblast cDNA expression library by screening with a polyclonal antiserum. The deduced amino acid (aa) sequence indicates that gp42 is a transmembrane protein of 273 aa with a large N-terminal portion exposed outside the cell and a short cytoplasmic domain. Computer assisted analysis shows that gp42 is distinct from previously characterized proteins, but shares a number of structural features with the class II histocompatibility antigens. The sizes of the extracellular domains of gp42 and of class II histocompatibility antigens are similar, the position of four cysteines and the location of several aa residues are conserved. Some of these conserved residues are also present in immunoglobulins (Ig) and in the neural-cell adhesion molecule, thus indicating that gp42 is a new member of the Ig superfamily.

    Gene 1989;85;2;445-51

Gene lists (4)

Gene List Source Species Name Description Gene count
L00000001 G2C Mus musculus Mouse PSD Mouse PSD adapted from Collins et al (2006) 1080
L00000008 G2C Mus musculus Mouse PSP Mouse PSP adapted from Collins et al (2006) 1121
L00000070 G2C Mus musculus BAYES-COLLINS-HUMAN-PSD-FULL Human cortex biopsy PSD full list (ortho) 1461
L00000072 G2C Mus musculus BAYES-COLLINS-MOUSE-PSD-FULL Mouse cortex PSD full list 1556
© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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