G2Cdb::Gene report

Gene id
G00000024
Gene symbol
Dab2ip (MGI)
Species
Mus musculus
Description
disabled homolog 2 (Drosophila) interacting protein
Orthologue
G00000049 (Homo sapiens)

Databases (8)

Curated Gene
OTTMUSG00000012149 (Vega mouse gene)
Gene
ENSMUSG00000026883 (Ensembl mouse gene)
69601 (Entrez Gene)
567 (G2Cdb plasticity & disease)
Gene Expression
MGI:1916851 (Allen Brain Atlas)
Literature
609205 (OMIM)
Marker Symbol
MGI:1916851 (MGI)
Protein Sequence
Q3UHC7 (UniProt)

Synonyms (1)

  • AIP1

Literature (18)

Pubmed - other

  • 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

  • Disabled-2 is required for mesoderm differentiation of murine embryonic stem cells.

    Huang CL, Cheng JC, Kitajima K, Nakano T, Yeh CF, Chong KY and Tseng CP

    Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan, Taiwan, Republic of China.

    A variety of signaling networks are implicated in the control of mesoderm differentiation. Previous studies demonstrated that Disabled-2 (DAB2) is a multifunctional protein involved in growth factor signaling and embryonic development. In this study, we investigated DAB2 expression and function during in vitro mesoderm differentiation of murine embryonic stem cells (ESCs). We found that DAB2 was up-regulated when ESCs were co-cultured with OP9 stromal cells for mesoderm differentiation. DAB2 was also up-regulated when ESCs were induced for embryoid body formation. Expression of DAB2 short hairpin small interfering RNA (shDAB2) did not alter the puripotency of ESCs. However, shDAB2 disrupted ESCs cell-cell adhesion and affected embryoid body and colony formation that subsequently impeded mesoderm differentiation of ESCs. Immunofluorescent staining revealed that disorganization of beta-catenin and plakoglobin cellular distribution may account for the aberrant cell-cell adhesion in DAB2-deficient cells. Accordingly, DAB2 was identified as a plakoglobin-binding partner with the interaction mediated by the phosphotyrosine binding domain of DAB2 and the Asn-Pro-Asp-Tyr (NPDY) motif of plakoglobin. Molecular analysis and transcriptome profiling also revealed that DAB2 was involved in the regulation of insulin-like growth factor 2-mediated signaling and in the expression of p53, asparagine synthetase and glutathione peroxidase 2. Expression screening of 52 ESCs-related miRNAs further unveiled the interplay between DAB2 and the signaling networks associated with cell death, differentiation and development. This study thereby defines a role of DAB2 in fate determination of ESCs and suggests the presence of a DAB2-associated regulatory circuit in the control of mesoderm differentiation.

    Journal of cellular physiology 2010;225;1;92-105

  • An oncogene-tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-kappaB.

    Min J, Zaslavsky A, Fedele G, McLaughlin SK, Reczek EE, De Raedt T, Guney I, Strochlic DE, Macconaill LE, Beroukhim R, Bronson RT, Ryeom S, Hahn WC, Loda M and Cichowski K

    Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    Metastasis is responsible for the majority of prostate cancer-related deaths; however, little is known about the molecular mechanisms that underlie this process. Here we identify an oncogene-tumor suppressor cascade that promotes prostate cancer growth and metastasis by coordinately activating the small GTPase Ras and nuclear factor-kappaB (NF-kappaB). Specifically, we show that loss of the Ras GTPase-activating protein (RasGAP) gene DAB2IP induces metastatic prostate cancer in an orthotopic mouse tumor model. Notably, DAB2IP functions as a signaling scaffold that coordinately regulates Ras and NF-kappaB through distinct domains to promote tumor growth and metastasis, respectively. DAB2IP is suppressed in human prostate cancer, where its expression inversely correlates with tumor grade and predicts prognosis. Moreover, we report that epigenetic silencing of DAB2IP is a key mechanism by which the polycomb-group protein histone-lysine N-methyltransferase EZH2 activates Ras and NF-kappaB and triggers metastasis. These studies define the mechanism by which two major pathways can be simultaneously activated in metastatic prostate cancer and establish EZH2 as a driver of metastasis.

    Funded by: NCI NIH HHS: K08 CA122833, K08 CA122833-05

    Nature medicine 2010;16;3;286-94

  • Role of DAB2IP in modulating epithelial-to-mesenchymal transition and prostate cancer metastasis.

    Xie D, Gore C, Liu J, Pong RC, Mason R, Hao G, Long M, Kabbani W, Yu L, Zhang H, Chen H, Sun X, Boothman DA, Min W and Hsieh JT

    Departmentsof Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

    A single nucleotide polymorphism in the DAB2IP gene is associated with risk of aggressive prostate cancer (PCa), and loss of DAB2IP expression is frequently detected in metastatic PCa. However, the functional role of DAB2IP in PCa remains unknown. Here, we show that the loss of DAB2IP expression initiates epithelial-to-mesenchymal transition (EMT), which is visualized by repression of E-cadherin and up-regulation of vimentin in both human normal prostate epithelial and prostate carcinoma cells as well as in clinical prostate-cancer specimens. Conversely, restoring DAB2IP in metastatic PCa cells reversed EMT. In DAB2IP knockout mice, prostate epithelial cells exhibited elevated mesenchymal markers, which is characteristic of EMT. Using a human prostate xenograft-mouse model, we observed that knocking down endogenous DAB2IP in human carcinoma cells led to the development of multiple lymph node and distant organ metastases. Moreover, we showed that DAB2IP functions as a scaffold protein in regulating EMT by modulating nuclear beta-catenin/T-cell factor activity. These results show the mechanism of DAB2IP in EMT and suggest that assessment of DAB2IP may provide a prognostic biomarker and potential therapeutic target for PCa metastasis.

    Funded by: NCI NIH HHS: P30 CA142543, R01 CA102792, R01 CA139217, U24 CA126608, U24CA126608; NIAID NIH HHS: 5U19AI067773-04, U19 AI067773

    Proceedings of the National Academy of Sciences of the United States of America 2010;107;6;2485-90

  • AIP1 functions as Arf6-GAP to negatively regulate TLR4 signaling.

    Wan T, Liu T, Zhang H, Tang S and Min W

    Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.

    Toll-like receptor 4 (TLR4) is unique among the Toll-like receptors in its ability to utilize TLR/IL1R-domain-containing adaptor protein (TIRAP), which recruits TLR4-MyD88 to phosphatidylinositol 4,5-bisphosphate (PIP(2))-rich sites on the plasma membrane, to activate NF-kappaB and MAPK pathways. Here, we show that AIP1 disrupts formation of the TLR4- TIRAP-MyD88 complex without directly binding to any of the complex components. AIP1 via its pleckstrin homology and C2 domains binds to phosphatidylinositol 4-phosphate, a lipid precursor of PIP(2). Knock-out of AIP1 in cells increases and overexpression of AIP1 reduces cellular PIP(2) levels. We further show that AIP1 is a novel GTPase-activating protein (GAP) for Arf6, a small GTPase regulating cellular PIP(2) production and formation of the TLR4-TIRAP-MyD88 complex. Thus, deletion of the GAP domain on AIP1 results in a loss of its ability to mediate the inhibition of Arf6- and TLR4-induced signaling events. We conclude that AIP1 functions as a novel Arf6-GAP to negatively regulate PIP(2)-dependent TLR4-TIRAP-MyD88 signaling.

    Funded by: NHLBI NIH HHS: P01 HL070295, P01HL070295-6, R01 HL-65978-5, R01 HL065978

    The Journal of biological chemistry 2010;285;6;3750-7

  • DAB2IP coordinates both PI3K-Akt and ASK1 pathways for cell survival and apoptosis.

    Xie D, Gore C, Zhou J, Pong RC, Zhang H, Yu L, Vessella RL, Min W and Hsieh JT

    Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

    In metastatic prostate cancer (PCa) cells, imbalance between cell survival and death signals such as constitutive activation of phosphatidylinositol 3-kinase (PI3K)-Akt and inactivation of apoptosis-stimulated kinase (ASK1)-JNK pathways is often detected. Here, we show that DAB2IP protein, often down-regulated in PCa, is a potent growth inhibitor by inducing G(0)/G(1) cell cycle arrest and is proapoptotic in response to stress. Gain of function study showed that DAB2IP can suppress the PI3K-Akt pathway and enhance ASK1 activation leading to cell apoptosis, whereas loss of DAB2IP expression resulted in PI3K-Akt activation and ASK1-JNK inactivation leading to accelerated PCa growth in vivo. Moreover, glandular epithelia from DAB2IP(-/-) animal exhibited hyperplasia and apoptotic defect. Structural functional analyses of DAB2IP protein indicate that both proline-rich (PR) and PERIOD-like (PER) domains, in addition to the critical role of C2 domain in ASK1 activity, are important for modulating PI3K-Akt activity. Thus, DAB2IP is a scaffold protein capable of bridging both survival and death signal molecules, which implies its role in maintaining cell homeostasis.

    Proceedings of the National Academy of Sciences of the United States of America 2009;106;47;19878-83

  • AIP1 functions as an endogenous inhibitor of VEGFR2-mediated signaling and inflammatory angiogenesis in mice.

    Zhang H, He Y, Dai S, Xu Z, Luo Y, Wan T, Luo D, Jones D, Tang S, Chen H, Sessa WC and Min W

    Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.

    ASK1-interacting protein-1 (AIP1), a recently identified member of the Ras GTPase-activating protein family, is highly expressed in vascular ECs and regulates EC apoptosis in vitro. However, its function in vivo has not been established. To study this, we generated AIP1-deficient mice (KO mice). Although these mice showed no obvious defects in vascular development, they exhibited dramatically enhanced angiogenesis in 2 models of inflammatory angiogenesis. In one of these models, the enhanced angiogenesis observed in the KO mice was associated with increased VEGF-VEGFR2 signaling. Consistent with this, VEGF-induced ear, cornea, and retina neovascularization were greatly augmented in KO mice and the enhanced retinal angiogenesis was markedly diminished by overexpression of AIP1. In vitro, VEGF-induced EC migration was inhibited by AIP1 overexpression, whereas it was augmented by both AIP1 knockout and knockdown, with the enhanced EC migration caused by AIP1 knockdown being associated with increased VEGFR2 signaling. We present mechanistic data that suggest AIP1 is recruited to the VEGFR2-PI3K complex, binding to both VEGFR2 and PI3K p85, at a late phase of the VEGF response, and that this leads to inhibition of VEGFR2 signaling. Taken together, our data demonstrate that AIP1 functions as an endogenous inhibitor in VEGFR2-mediated adaptive angiogenesis in mice.

    Funded by: NCI NIH HHS: F31 CA 136316, F31 CA136316; NHLBI NIH HHS: P01 HL070295, P01HL070295-6, R01 HL-65978-5, R01 HL065978, R01 HL077357, R01 HL077357-1, R01 HL093242

    The Journal of clinical investigation 2008;118;12;3904-16

  • AIP1 is critical in transducing IRE1-mediated endoplasmic reticulum stress response.

    Luo D, He Y, Zhang H, Yu L, Chen H, Xu Z, Tang S, Urano F and Min W

    Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.

    We have previously shown that ASK1-interacting protein 1 (AIP1) transduces tumor necrosis factor-induced ASK1-JNK signaling. Because endoplasmic reticulum (ER) stress activates ASK1-JNK signaling cascade, we investigated the role of AIP1 in ER stress-induced signaling. We created AIP1-deficient mice (AIP1-KO) from which mouse embryonic fibroblasts and vascular endothelial cells were isolated. AIP1-KO cells show dramatic reductions in ER stress-induced, but not oxidative stress-induced, ASK1-JNK activation and cell apoptosis. The ER stress-induced IRE1-JNK/XBP-1 axis, but not the PERK-CHOP1 axis, is blunted in AIP1-KO cells. ER stress induced formation of an AIP1-IRE1 complex, and the PH domain of AIP1 is critical for the IRE1 interaction. Furthermore, reconstitution of AIP1-KO cells with AIP1 wild type, not an AIP1 mutant with a deletion of the PH domain (AIP1-DeltaPH), restores ER stress-induced IRE1-JNK/XBP-1 signaling. AIP1-IRE1 association facilitates IRE1 dimerization, a critical step for activation of IRE1 signaling. More importantly, AIP1-KO mice show impaired ER stress-induced IRE1-dependent signaling in vivo. We conclude that AIP1 is essential for transducing the IRE1-mediated ER stress response.

    Funded by: NHLBI NIH HHS: P01 HL070295-6, R01 HL077357-1, R01 HL65978-05

    The Journal of biological chemistry 2008;283;18;11905-12

  • Qualitative and quantitative analyses of protein phosphorylation in naive and stimulated mouse synaptosomal preparations.

    Munton RP, Tweedie-Cullen R, Livingstone-Zatchej M, Weinandy F, Waidelich M, Longo D, Gehrig P, Potthast F, Rutishauser D, Gerrits B, Panse C, Schlapbach R and Mansuy IM

    Brain Research Institute, Medical Faculty of the University of Zürich, Switzerland.

    Activity-dependent protein phosphorylation is a highly dynamic yet tightly regulated process essential for cellular signaling. Although recognized as critical for neuronal functions, the extent and stoichiometry of phosphorylation in brain cells remain undetermined. In this study, we resolved activity-dependent changes in phosphorylation stoichiometry at specific sites in distinct subcellular compartments of brain cells. Following highly sensitive phosphopeptide enrichment using immobilized metal affinity chromatography and mass spectrometry, we isolated and identified 974 unique phosphorylation sites on 499 proteins, many of which are novel. To further explore the significance of specific phosphorylation sites, we used isobaric peptide labels and determined the absolute quantity of both phosphorylated and non-phosphorylated peptides of candidate phosphoproteins and estimated phosphorylation stoichiometry. The analyses of phosphorylation dynamics using differentially stimulated synaptic terminal preparations revealed activity-dependent changes in phosphorylation stoichiometry of target proteins. Using this method, we were able to differentiate between distinct isoforms of Ca2+/calmodulin-dependent protein kinase (CaMKII) and identify a novel activity-regulated phosphorylation site on the glutamate receptor subunit GluR1. Together these data illustrate that mass spectrometry-based methods can be used to determine activity-dependent changes in phosphorylation stoichiometry on candidate phosphopeptides following large scale phosphoproteome analysis of brain tissue.

    Molecular & cellular proteomics : MCP 2007;6;2;283-93

  • Cloning of mouse Dab2ip gene, a novel member of the RasGTPase-activating protein family and characterization of its regulatory region in prostate.

    Chen H, Karam JA, Schultz R, Zhang Z, Duncan C and Hsieh JT

    Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    Disabled homolog 2 (Drosophila) interacting protein (DAB2IP/Dab2IP) is a member of the GTPase-activating protein for downregulating the Ras-mediated signal pathway and TNF-mediated apoptosis. The downregulation of human DAB2IP mRNA levels was detected in prostate cancer cells due to the epigenetic regulation. Here, we isolated a mouse Dab2ip gene with a highly homologous sequence to that of the human and rat gene and mapped it at chromosome 2B. The mDab2ip gene contains 14 exons and 13 introns and spans approximately 65 kb. Exon1 contains at least three splicing variants (Ia, Ib, and Ic). The deduced amino acid sequence of mouse Dab2IP encompasses 1065 residues containing several unique protein interaction motifs as well as a Ras-like GAP-related domain, which shares a high homology with both humans and rats. Data from real-time RT-PCR analysis revealed a diverse expression pattern of the mDab2ip gene in various organs, implying differential regulation of this gene from various tissues. We have mapped a 1.3-kb segment containing a 5'-upstream region from exon Ia as a promoter region (-147/+545) in prostatic epithelial cell lines (TRAMP-C); this region is highly GC-rich, and mDab2ip appears to be a TATA-less promoter. It appears that epigenetic regulation, particularly histone acetylation of the Dab2ip gene promoter, plays an important role in modulating its gene expression in the mouse prostate cancer cell.

    DNA and cell biology 2006;25;4;232-45

  • Construction of a multi-functional cDNA library specific for mouse pancreatic islets and its application to microarray.

    Nishimura M, Yokoi N, Miki T, Horikawa Y, Yoshioka H, Takeda J, Ohara O and Seino S

    Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.

    We have constructed a high-quality and multi-applicable cDNA library specific for mouse pancreatic islets. This is the first pancreatic islet cDNA library created using a recombination-based method, which can readily be converted into other applications including yeast two-hybrid and mammalian expression libraries. Based on sequence data of the library, we constructed a sequence database specific for mouse pancreatic islets. Among the 8882 non-redundant clones, 5799 were classified into specific functional categories using a classification system designed by the Gene Ontology Consortium, 10% of which were "molecular function unknown" genes. We also developed cDNA microarray membranes with 8108 non-redundant clones. Analyses of expression profiles of three different cell lines and of MIN6 cells with or without overexpression of transcription factor NeuroD1 established the usefulness and applicability of our microarrays. The mouse pancreatic islet cDNA library, sequence database, set of clones, and microarrays developed in this study should be useful resources for studies of pancreatic islets and related diseases including diabetes mellitus.

    DNA research : an international journal for rapid publication of reports on genes and genomes 2004;11;5;315-23

  • 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

  • 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

  • Interaction of Disabled-1 and the GTPase activating protein Dab2IP in mouse brain.

    Homayouni R, Magdaleno S, Keshvara L, Rice DS and Curran T

    Department of Neurology, University of Tennessee, 855 Monroe Avenue, 416 Link Building, Memphis, TN 38163, USA. rhomayouni@utmem.edu

    The Reelin signaling pathway controls neuronal positioning during mammalian brain development by binding to the very low density lipoprotein receptor and apolipoprotein E receptor-2, and signaling through the intracellular adapter protein Disabled-1 (Dab1). To identify new components in the Reelin signaling pathway, we used a yeast two-hybrid screen to select Dab1-interacting proteins. Here, we report the characterization of a new mouse Dab1-interacting protein that is orthologous to rat Dab2IP, a Ras-GTPase activating protein previously shown to bind to Dab2/DOC. The interaction of Dab1 and Dab2IP was confirmed in biochemical assays and by co-immunoprecipitation from brain lysates. The site of interaction between Dab1 and Dab2IP was narrowed to the Dab1-PTB domain and the NPxY motif in Dab2IP. The deduced amino acid sequence of mouse Dab2IP encompasses 1,208 residues containing several protein interaction motifs as well as a Ras-like GAP-related domain. Northern blot analysis revealed at least two isoforms of Dab2IP mRNA in the brain, both of which exhibited increased expression during development. In situ hybridization analyses indicated that Dab2IP mRNA is diffusely expressed throughout the developing and the adult brain. Using a polyclonal antiserum specific for Dab2IP, we observed protein expression in the soma and processes of neurons in a variety of brain structures, including the developing cerebral cortex. Our findings suggest that Dab2IP may function as a downstream effector in the Reelin signaling pathway that influences Ras signaling during brain development.

    Funded by: NCI NIH HHS: P30 CA21765; NINDS NIH HHS: R01-NS36558; PHS HHS: 06972

    Brain research. Molecular brain research 2003;115;2;121-9

  • Prediction of the coding sequences of mouse homologues of KIAA gene: II. The complete nucleotide sequences of 400 mouse KIAA-homologous cDNAs identified by screening of terminal sequences of cDNA clones randomly sampled from size-fractionated libraries.

    Okazaki N, Kikuno R, Ohara R, Inamoto S, Aizawa H, Yuasa S, Nakajima D, Nagase T, Ohara O and Koga H

    Kazusa DNA Research Institute, 2-6-7 Kazusa-Kamatari, Kisarazu, Chiba 292-0818, Japan.

    We have accumulated information of the coding sequences of uncharacterized human genes, which are known as KIAA genes, and the number of these genes exceeds 2000 at present. As an extension of this sequencing project, we recently have begun to accumulate mouse KIAA-homologous cDNAs, because it would be useful to prepare a set of human and mouse homologous cDNA pairs for further functional analysis of the KIAA genes. We herein present the entire sequences of 400 mouse KIAA cDNA clones and 4 novel cDNA clones which were incidentally identified during this project. Most of clones entirely sequenced in this study were selected by computer-assisted analysis of terminal sequences of the cDNAs. The average size of the 404 cDNA sequences reached 5.3 kb and that of the deduced amino acid sequences from these cDNAs was 868 amino acid residues. The results of sequence analyses of these clones showed that single mouse KIAA cDNAs bridged two different human KIAA cDNAs in some cases, which indicated that these two human KIAA cDNAs were derived from single genes although they had been supposed to originate from different genes. Furthermore, we successfully mapped all the mouse KIAA cDNAs along the genome using a recently published mouse genome draft sequence.

    DNA research : an international journal for rapid publication of reports on genes and genomes 2003;10;1;35-48

  • BayGenomics: a resource of insertional mutations in mouse embryonic stem cells.

    Stryke D, Kawamoto M, Huang CC, Johns SJ, King LA, Harper CA, Meng EC, Lee RE, Yee A, L'Italien L, Chuang PT, Young SG, Skarnes WC, Babbitt PC and Ferrin TE

    Department of Pharmaceutical Chemistry, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA.

    The BayGenomics gene-trap resource (http://baygenomics.ucsf.edu) provides researchers with access to thousands of mouse embryonic stem (ES) cell lines harboring characterized insertional mutations in both known and novel genes. Each cell line contains an insertional mutation in a specific gene. The identity of the gene that has been interrupted can be determined from a DNA sequence tag. Approximately 75% of our cell lines contain insertional mutations in known mouse genes or genes that share strong sequence similarities with genes that have been identified in other organisms. These cell lines readily transmit the mutation to the germline of mice and many mutant lines of mice have already been generated from this resource. BayGenomics provides facile access to our entire database, including sequence tags for each mutant ES cell line, through the World Wide Web. Investigators can browse our resource, search for specific entries, download any portion of our database and BLAST sequences of interest against our entire set of cell line sequence tags. They can then obtain the mutant ES cell line for the purpose of generating knockout mice.

    Funded by: NCRR NIH HHS: P41 RR001081, P41 RR01081; NHLBI NIH HHS: U01 HL066621, U01 HL66621

    Nucleic acids research 2003;31;1;278-81

  • Construction of long-transcript enriched cDNA libraries from submicrogram amounts of total RNAs by a universal PCR amplification method.

    Piao Y, Ko NT, Lim MK and Ko MS

    Developmental Genomics and Aging Section, Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.

    Here we report a novel design of linker primer that allows one to differentially amplify long tracts (average 3.0 kb with size ranges of 1-7 kb) or short DNAs (average 1.5 kb with size ranges of 0.5-3 kb) from a complex mixture. The method allows one to generate cDNA libraries enriched for long transcripts without size selection of insert DNAs. One representative library from newborn kidney includes 70% of clones bearing ATG start codons. A comparable library has been generated from 20 mouse blastocysts, containing only approximately 40 ng of total RNA. This universal PCR amplification scheme can provide a route to isolate very large cDNAs, even if they are expressed at very low levels.

    Genome research 2001;11;9;1553-8

  • 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

Gene lists (5)

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
L00000062 G2C Mus musculus BAYES-COLLINS-MOUSE-PSD-CONSENSUS Mouse cortex PSD consensus 984
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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