G2Cdb::Gene report

Gene id
G00001369
Gene symbol
HOMER1 (HGNC)
Species
Homo sapiens
Description
homer homolog 1 (Drosophila)
Orthologue
G00000120 (Mus musculus)

Databases (8)

Gene
ENSG00000152413 (Ensembl human gene)
9456 (Entrez Gene)
35 (G2Cdb plasticity & disease)
HOMER1 (GeneCards)
Literature
604798 (OMIM)
Marker Symbol
HGNC:17512 (HGNC)
Protein Expression
4437 (human protein atlas)
Protein Sequence
Q86YM7 (UniProt)

Synonyms (3)

  • HOMER-1B
  • SYN47
  • Ves-1

Diseases (3)

Disease Nervous effect Mutations Found Literature Mutations Type Genetic association?
D00000166: Schizophrenia Y Y (12815733) Single nucleotide polymorphism (SNP) N
D00000164: Cocaine dependence Y Y (16314758) Single nucleotide polymorphism (SNP) Y
D00000276: Preeclampsia N Y (16202503) Single nucleotide polymorphism (SNP) N

References

  • Is preeclampsia associated with higher frequency of HSP70 gene polymorphisms?

    Fekete A, Vér A, Bögi K, Treszl A and Rigó J

    Research Laboratory for Pediatrics and Nephrology, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary.

    Aim: To evaluate the possible association of three different HSP70 gene polymorphisms with preeclampsia.

    HSPA1A G(190)C, HSPA1B A(1267)G and HSPA1L T(2437)C polymorphisms were analyzed from blood samples of 72 women with preeclampsia and of 70 healthy pregnant women as controls by PCR-RFLP method.

    Results: HSPA1B (1267)GG and HSPA1L (2437)CC genotypes occurred more frequently in preeclamptic patients compared to healthy controls (p<0.002 [RR: 4.38, 95% CI: 1.56-12.28]) and (p<0.03 [RR: 1.31, 95% CI: 1.03-1.67]), respectively. Significant difference was found in the distribution of HSPA1B A(1267)G genotype between the preeclamptic and control group (p<0.004 [RR: 0.67, 95% CI: 0.51-0.88]). Distribution of HSPA1A G(190)C was similar in the preeclamptic and control group. In controls, genotype distribution of HSPA1A G(190)C and HSPA1L T(2437)C was in Hardy-Weinberg equilibrium, while this criterion was not fulfilled for HSPA1B A(1267)G.

    Conclusion: We concluded that HSPA1B (1267)GG and HSPA1L (2437)CC genotypes were more frequent among preeclamptic than control patients, suggesting that these genotypes may play a role in the susceptibility for preeclampsia.

    European journal of obstetrics, gynecology, and reproductive biology 2006;126;2;197-200

  • Association of a polymorphism in the Homer1 gene with cocaine dependence in an African American population.

    Dahl JP, Kampman KM, Oslin DW, Weller AE, Lohoff FW, Ferraro TN, O'Brien CP and Berrettini WH

    Department of Psychiatry, Center for Neurobiology and Behavior, University of Pennsylvania School of Medicine, Clinical Research Building, Philadelphia, 19104, USA. jdahl@mail.med.upenn.edu

    Objective: While twin and adoption studies have demonstrated that up to 70% of the risk for becoming addicted to cocaine is due to genetic factors, identifying specific genes involved in the development or progression of cocaine dependence has been difficult. The purpose of this study is to determine whether single-nucleotide polymorphisms in the Homer1 and Homer2 genes associate with the cocaine-dependent phenotype in an African American population.

    Methods: This study utilized a case-control design in which the genotype and allele frequencies for four single-nucleotide polymorphisms in the Homer1 gene and three single-nucleotide polymorphisms in the Homer2 gene were compared between African American individuals with a diagnosis of cocaine dependence (n=170) and African American individuals with no history of substance abuse (n=90).

    Results: The data indicate that one single-nucleotide polymorphism, rs6871510, located in intron 1 of the Homer1 gene significantly (P=0.029) associates with cocaine dependence at the genotype level, and trends toward a significant association at the allele frequency level (chi=2.62, df=1, P=0.106, OR=1.71). None of the single-nucleotide polymorphisms analyzed in the Homer2 gene associates with cocaine dependence.

    Conclusions: The results of this study suggest that a polymorphism in the Homer1 gene, rs6871510, is a potential risk factor for the development of cocaine dependence in an African American population, whereas polymorphisms in the Homer2 gene are not.

    Funded by: NIDA NIH HHS: T32 DA07241-12; PHS HHS: P60-051186

    Psychiatric genetics 2005;15;4;277-83

  • Mutation screening of the Homer gene family and association analysis in schizophrenia.

    Norton N, Williams HJ, Williams NM, Spurlock G, Zammit S, Jones G, Jones S, Owen R, O'Donovan MC and Owen MJ

    Department of Psychological Medicine, University of Wales College of Medicine, Heath Park, Cardiff, United Kingdom.

    Homer proteins are a group of proteins that regulate group 1 metabotropic glutamate receptor function. As altered glutamate function has been implicated in many neuro psychiatric disorders, particularly schizophrenia, we have screened all three known Homer genes for sequence variation for use under the candidate gene association paradigm. We found seven SNPs, including three in exons. Of these, none was non-synonymous. Allele frequencies of all the detected SNPs were estimated in DNA pools of 368 schizophrenics and 368 controls. Only one (Homer 1 IVS4 + 18A > G) was associated with schizophrenia in this sample, a finding confirmed by individual genotyping (P = 0.01). However, in our extended sample of 680 cases and 671 controls, the evidence for association diminished (P = 0.05). Our results suggest it is unlikely that sequence variants in the Homer genes contribute to the aetiology of schizophrenia, but the variants we identified are plausible candidates for other neuropsychiatric phenotypes.

    Funded by: Medical Research Council: G9309834, G9810900

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2003;120B;1;18-21

Literature (35)

Pubmed - human_disease

  • Is preeclampsia associated with higher frequency of HSP70 gene polymorphisms?

    Fekete A, Vér A, Bögi K, Treszl A and Rigó J

    Research Laboratory for Pediatrics and Nephrology, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary.

    Aim: To evaluate the possible association of three different HSP70 gene polymorphisms with preeclampsia.

    HSPA1A G(190)C, HSPA1B A(1267)G and HSPA1L T(2437)C polymorphisms were analyzed from blood samples of 72 women with preeclampsia and of 70 healthy pregnant women as controls by PCR-RFLP method.

    Results: HSPA1B (1267)GG and HSPA1L (2437)CC genotypes occurred more frequently in preeclamptic patients compared to healthy controls (p<0.002 [RR: 4.38, 95% CI: 1.56-12.28]) and (p<0.03 [RR: 1.31, 95% CI: 1.03-1.67]), respectively. Significant difference was found in the distribution of HSPA1B A(1267)G genotype between the preeclamptic and control group (p<0.004 [RR: 0.67, 95% CI: 0.51-0.88]). Distribution of HSPA1A G(190)C was similar in the preeclamptic and control group. In controls, genotype distribution of HSPA1A G(190)C and HSPA1L T(2437)C was in Hardy-Weinberg equilibrium, while this criterion was not fulfilled for HSPA1B A(1267)G.

    Conclusion: We concluded that HSPA1B (1267)GG and HSPA1L (2437)CC genotypes were more frequent among preeclamptic than control patients, suggesting that these genotypes may play a role in the susceptibility for preeclampsia.

    European journal of obstetrics, gynecology, and reproductive biology 2006;126;2;197-200

Pubmed - other

  • Identification of new putative susceptibility genes for several psychiatric disorders by association analysis of regulatory and non-synonymous SNPs of 306 genes involved in neurotransmission and neurodevelopment.

    Gratacòs M, Costas J, de Cid R, Bayés M, González JR, Baca-García E, de Diego Y, Fernández-Aranda F, Fernández-Piqueras J, Guitart M, Martín-Santos R, Martorell L, Menchón JM, Roca M, Sáiz-Ruiz J, Sanjuán J, Torrens M, Urretavizcaya M, Valero J, Vilella E, Estivill X, Carracedo A and Psychiatric Genetics Network Group

    CIBER en Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain.

    A fundamental difficulty in human genetics research is the identification of the spectrum of genetic variants that contribute to the susceptibility to common/complex disorders. We tested here the hypothesis that functional genetic variants may confer susceptibility to several related common disorders. We analyzed five main psychiatric diagnostic categories (substance-abuse, anxiety, eating, psychotic, and mood disorders) and two different control groups, representing a total of 3,214 samples, for 748 promoter and non-synonymous single nucleotide polymorphisms (SNPs) at 306 genes involved in neurotransmission and/or neurodevelopment. We identified strong associations to individual disorders, such as growth hormone releasing hormone (GHRH) with anxiety disorders, prolactin regulatory element (PREB) with eating disorders, ionotropic kainate glutamate receptor 5 (GRIK5) with bipolar disorder and several SNPs associated to several disorders, that may represent individual and related disease susceptibility factors. Remarkably, a functional SNP, rs945032, located in the promoter region of the bradykinin receptor B2 gene (BDKRB2) was associated to three disorders (panic disorder, substance abuse, and bipolar disorder), and two additional BDKRB2 SNPs to obsessive-compulsive disorder and major depression, providing evidence for common variants of susceptibility to several related psychiatric disorders. The association of BDKRB2 (odd ratios between 1.65 and 3.06) to several psychiatric disorders supports the view that a common genetic variant could confer susceptibility to clinically related phenotypes, and defines a new functional hint in the pathophysiology of psychiatric diseases.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2009;150B;6;808-16

  • Homer1 regulates the susceptibility to TRAIL.

    Shin JN, Piya S, Yun CW, Seol DW, Seo YW, Moon AR and Kim TH

    Department of Biochemistry, Chosun University School of Medicine, 375 Seosuk-Dong, Dong-Gu, Gwangju, 501-759, Republic of Korea.

    TRAIL is an apoptotic cell death-inducing ligand that belongs to a TNF superfamily. To identify the regulators that govern the susceptibility to TRAIL, TRAIL-resistant HeLa (TR) cells were established by repeatedly treating HeLa cells with TRAIL. Here we showed that scaffolding protein Homer1 plays a decisive role in regulating the apoptotic susceptibility to TRAIL. TR cells showing the normal susceptibility to FasL and chemotherapeutic agent etoposide expressed the lower protein levels of Homer1 than parental HeLa cells. They showed the delayed activation of caspases-8, Bid cleavage and Bax translocation to mitochondria in response to TRAIL. Reconstitution of Homer1 expression in TR cells significantly restored the susceptibility to TRAIL. In addition, knock-down of Homer1 using interfering shRNA in parental HeLa cells lost the susceptibility to TRAIL. Together, our data indicate that Homer1 plays a critical role in determining the apoptotic susceptibility to TRAIL.

    Experimental cell research 2009;315;13;2249-55

  • Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia.

    Martins-de-Souza D, Gattaz WF, Schmitt A, Rewerts C, Maccarrone G, Dias-Neto E and Turck CW

    Laboratório de Neurociências, Instituto de Psiquiatria, Universidade de São Paulo, Rua. Dr. Ovidio Pires de Campos, no 785, Consolação, São Paulo, SP 05403-010, Brazil.

    Schizophrenia is a complex disease, likely to be caused by a combination of serial alterations in a number of genes and environmental factors. The dorsolateral prefrontal cortex (Brodmann's Area 46) is involved in schizophrenia and executes high-level functions such as working memory, differentiation of conflicting thoughts, determination of right and wrong concepts and attitudes, correct social behavior and personality expression. Global proteomic analysis of post-mortem dorsolateral prefrontal cortex samples from schizophrenia patients and non-schizophrenic individuals was performed using stable isotope labeling and shotgun proteomics. The analysis resulted in the identification of 1,261 proteins, 84 of which showed statistically significant differential expression, reinforcing previous data supporting the involvement of the immune system, calcium homeostasis, cytoskeleton assembly, and energy metabolism in schizophrenia. In addition a number of new potential markers were found that may contribute to the understanding of the pathogenesis of this complex disease.

    European archives of psychiatry and clinical neuroscience 2009;259;3;151-63

  • HOMER1 promoter analysis in Parkinson's disease: association study with psychotic symptoms.

    De Luca V, Annesi G, De Marco EV, de Bartolomeis A, Nicoletti G, Pugliese P, Muscettola G, Barone P and Quattrone A

    Department of Neuroscience and Behavioural Sciences, Section of Psychiatry, Naples, Italy.

    Aims: HOMER1 gene expression has been linked to abnormal movements in animals receiving chronic administration of antipsychotics. The continuing neurodegeneration of Parkinson's disease (PD) and the prolonged use of L-dopa are associated with motor complications, such as dyskinesia, and psychotic side effects, including hallucinations and paranoid delusions. Approximately 25-40% of patients with idiopathic PD experience hallucinations. Genetic variability within different candidate genes has been implicated in the clinical severity of sporadic PD in many populations.

    We investigated 3 polymorphisms located in the 5' flanking region of the HOMER1 gene within a sample of 131 sporadic PD patients from southern Italy, using a 3-SNP genotype and haplotype combination (rs4704559, rs10942891, rs4704560).

    Results: Our study implicates the effects of allele A of the rs4704559 marker in susceptibility to psychotic symptoms in PD (chi2 = 8.092, 1 d.f., p = 0.004).

    Conclusion: Even though our results are preliminary, this HOMER1 gene variant may represent a biomarker for side effect evaluation in PD patients.

    Neuropsychobiology 2009;59;4;239-45

  • Common variants in the GDF5-UQCC region are associated with variation in human height.

    Sanna S, Jackson AU, Nagaraja R, Willer CJ, Chen WM, Bonnycastle LL, Shen H, Timpson N, Lettre G, Usala G, Chines PS, Stringham HM, Scott LJ, Dei M, Lai S, Albai G, Crisponi L, Naitza S, Doheny KF, Pugh EW, Ben-Shlomo Y, Ebrahim S, Lawlor DA, Bergman RN, Watanabe RM, Uda M, Tuomilehto J, Coresh J, Hirschhorn JN, Shuldiner AR, Schlessinger D, Collins FS, Davey Smith G, Boerwinkle E, Cao A, Boehnke M, Abecasis GR and Mohlke KL

    Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.

    Identifying genetic variants that influence human height will advance our understanding of skeletal growth and development. Several rare genetic variants have been convincingly and reproducibly associated with height in mendelian syndromes, and common variants in the transcription factor gene HMGA2 are associated with variation in height in the general population. Here we report genome-wide association analyses, using genotyped and imputed markers, of 6,669 individuals from Finland and Sardinia, and follow-up analyses in an additional 28,801 individuals. We show that common variants in the osteoarthritis-associated locus GDF5-UQCC contribute to variation in height with an estimated additive effect of 0.44 cm (overall P < 10(-15)). Our results indicate that there may be a link between the genetic basis of height and osteoarthritis, potentially mediated through alterations in bone growth and development.

    Funded by: Intramural NIH HHS; Medical Research Council: G0000934, G0600705; NCRR NIH HHS: M01 RR 16500, M01 RR016500; NHGRI NIH HHS: HG002651, N01HG65403, R01 HG002651, R01 HG002651-05S2, Z01 HG000024; NHLBI NIH HHS: HL084729, HL72515, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, N01HC55015, N01HC55016, N01HC55018, N01HC55019, N01HC55020, N01HC55021, N01HC55022, U01 HL072515, U01 HL084729, U01 HL084729-03; NIA NIH HHS: AG18728, R01 AG018728; NIAMS NIH HHS: AR046838, R01 AR046838; NIDDK NIH HHS: DK062370, DK072193, DK54361, P30 DK072488, R01 DK029867, R01 DK062370, R01 DK072193, R01 DK072193-04, R56 DK062370, U01 DK062370; Wellcome Trust: 068545/Z/02

    Nature genetics 2008;40;2;198-203

  • The intracellular domain of the human protocadherin hFat1 interacts with Homer signalling scaffolding proteins.

    Schreiner D, Müller K and Hofer HW

    Department of Biology, University of Konstanz, AG Hofer, P.O. Box M648, D-78457 Konstanz, Germany. dietmar.schreiner@uni-konstanz.de

    The cadherin superfamily protein Fat1 is known to interact with the EVH1 domain of mammalian Ena/VASP. Here we demonstrate that: (i) the scaffolding proteins Homer-3 and Homer-1 also interact with the EVH1 binding site of hFat1 in vitro, and (ii) binding of Homer-3 and Mena to hFat1 is mutually competitive. Endogenous Fat1 binds to immobilised Homer-3 and endogenous Homer-3 binds to immobilised Fat1. Both, endogenous and over-expressed Fat1 exhibit co-localisation with Homer-3 in cellular protrusions and at the plasma membrane of HeLa cells. As Homer proteins and Fat1 have been both linked to psychic disorders, their interaction may be of patho-physiological importance.

    FEBS letters 2006;580;22;5295-300

  • Association of a polymorphism in the Homer1 gene with cocaine dependence in an African American population.

    Dahl JP, Kampman KM, Oslin DW, Weller AE, Lohoff FW, Ferraro TN, O'Brien CP and Berrettini WH

    Department of Psychiatry, Center for Neurobiology and Behavior, University of Pennsylvania School of Medicine, Clinical Research Building, Philadelphia, 19104, USA. jdahl@mail.med.upenn.edu

    Objective: While twin and adoption studies have demonstrated that up to 70% of the risk for becoming addicted to cocaine is due to genetic factors, identifying specific genes involved in the development or progression of cocaine dependence has been difficult. The purpose of this study is to determine whether single-nucleotide polymorphisms in the Homer1 and Homer2 genes associate with the cocaine-dependent phenotype in an African American population.

    Methods: This study utilized a case-control design in which the genotype and allele frequencies for four single-nucleotide polymorphisms in the Homer1 gene and three single-nucleotide polymorphisms in the Homer2 gene were compared between African American individuals with a diagnosis of cocaine dependence (n=170) and African American individuals with no history of substance abuse (n=90).

    Results: The data indicate that one single-nucleotide polymorphism, rs6871510, located in intron 1 of the Homer1 gene significantly (P=0.029) associates with cocaine dependence at the genotype level, and trends toward a significant association at the allele frequency level (chi=2.62, df=1, P=0.106, OR=1.71). None of the single-nucleotide polymorphisms analyzed in the Homer2 gene associates with cocaine dependence.

    Conclusions: The results of this study suggest that a polymorphism in the Homer1 gene, rs6871510, is a potential risk factor for the development of cocaine dependence in an African American population, whereas polymorphisms in the Homer2 gene are not.

    Funded by: NIDA NIH HHS: T32 DA07241-12; PHS HHS: P60-051186

    Psychiatric genetics 2005;15;4;277-83

  • Towards a proteome-scale map of the human protein-protein interaction network.

    Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP and Vidal M

    Center for Cancer Systems Biology and Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA.

    Systematic mapping of protein-protein interactions, or 'interactome' mapping, was initiated in model organisms, starting with defined biological processes and then expanding to the scale of the proteome. Although far from complete, such maps have revealed global topological and dynamic features of interactome networks that relate to known biological properties, suggesting that a human interactome map will provide insight into development and disease mechanisms at a systems level. Here we describe an initial version of a proteome-scale map of human binary protein-protein interactions. Using a stringent, high-throughput yeast two-hybrid system, we tested pairwise interactions among the products of approximately 8,100 currently available Gateway-cloned open reading frames and detected approximately 2,800 interactions. This data set, called CCSB-HI1, has a verification rate of approximately 78% as revealed by an independent co-affinity purification assay, and correlates significantly with other biological attributes. The CCSB-HI1 data set increases by approximately 70% the set of available binary interactions within the tested space and reveals more than 300 new connections to over 100 disease-associated proteins. This work represents an important step towards a systematic and comprehensive human interactome project.

    Funded by: NCI NIH HHS: R33 CA132073; NHGRI NIH HHS: P50 HG004233, R01 HG001715, RC4 HG006066, U01 HG001715; NHLBI NIH HHS: U01 HL098166

    Nature 2005;437;7062;1173-8

  • Interactions between ephrin-B and metabotropic glutamate 1 receptors in brain tissue and cultured neurons.

    Calò L, Bruno V, Spinsanti P, Molinari G, Korkhov V, Esposito Z, Patanè M, Melchiorri D, Freissmuth M and Nicoletti F

    Department of Human Physiology and Pharmacology, University of Rome La Sapienza, 00185 Rome, Italy.

    We examined the interaction between ephrins and metabotropic glutamate (mGlu) receptors in the developing brain and cultured neurons. EphrinB2 coimmunoprecipitated with mGlu1a receptors, in all of the brain regions examined, and with mGlu5 receptors in the corpus striatum. In striatal slices, activation of ephrinB2 by a clustered form of its target receptor, EphB1, amplified the mGlu receptor-mediated stimulation of polyphosphoinositide (PI) hydrolysis. This effect was abolished in slices treated with mGlu1 or NMDA receptor antagonists but was not affected by pharmacological blockade of mGlu5 receptors. An interaction among ephrinB2, mGlu1 receptor, and NMDA was supported by the following observations: (1) the NR1 subunit of NMDA receptors coimmunoprecipitated with mGlu1a receptors and ephrinB2 in striatal lysates; (2) clustered EphB1 amplified excitatory amino acid-stimulated PI hydrolysis in cultured granule cells grown under conditions that favored the expression of mGlu1a receptors; and (3) clustered EphB1 amplified the enhancing effect of mGlu receptor agonists on NMDA toxicity in cortical cultures, and its action was sensitive to mGlu1 receptor antagonists. Finally, fluorescence resonance energy transfer and coclustering analysis in human embryonic kidney 293 cells excluded a physical interaction between ephrinB2 and mGlu1a (or mGlu5 receptors). A functional interaction between ephrinB and mGlu1 receptors, which likely involves adaptor or scaffolding proteins, might have an important role in the regulation of developmental plasticity.

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2005;25;9;2245-54

  • AAV-mediated hippocampal expression of short and long Homer 1 proteins differentially affect cognition and seizure activity in adult rats.

    Klugmann M, Symes CW, Leichtlein CB, Klaussner BK, Dunning J, Fong D, Young D and During MJ

    Department of Molecular Medicine and Pathology, Functional Genomics and Translational Neuroscience Laboratory, University of Auckland, Auckland, New Zealand. m.klugmann@auckland.ac.nz

    Homer proteins mediate molecular rearrangements leading to changes in spine morphology. This points to a role of Homer in learning and memory. Homer 1c features both the ligand binding domain and a coiled-coiled domain for self-multimerization. Homer 1a lacks the coiled-coiled domain. Here, we report a new isoform which we termed 1g, lacking the Homer ligand binding domain. We dissected the functional roles of the individual Homer 1 domains, encoded by Homer 1a, 1c, and 1g, in vivo. Recombinant adeno-associated virus (AAV)-mediated overexpression of these forms in the hippocampus of adult rats has opposing effects on learning behavior. Increased levels of Homer 1a impaired hippocampal-dependent memory, while Homer 1g and 1c slightly enhanced memory performance. Homer 1g induced anxiety. Moreover, AAV-Homer 1a animals showed attenuation of electrographic seizures in a model of status epilepticus. These results suggest that Homer 1 proteins play an active role in behavioral plasticity.

    Molecular and cellular neurosciences 2005;28;2;347-60

  • A novel scaffold protein, TANC, possibly a rat homolog of Drosophila rolling pebbles (rols), forms a multiprotein complex with various postsynaptic density proteins.

    Suzuki T, Li W, Zhang JP, Tian QB, Sakagami H, Usuda N, Usada N, Kondo H, Fujii T and Endo S

    Department of Neuroplasticity, Institute on Ageing and Adaptation, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan. suzukit@sch.md.shinshu-u.ac.jp

    We cloned from the rat brain a novel gene, tanc (GenBank Accession No. AB098072), which encoded a protein containing three tetratricopeptide repeats (TPRs), ten ankyrin repeats and a coiled-coil region, and is possibly a rat homolog of Drosophila rolling pebbles (rols). The tanc gene was expressed widely in the adult rat brain. Subcellular distribution, immunohistochemical study of the brain and immunocytochemical studies of cultured neuronal cells indicated the postsynaptic localization of TANC protein of 200 kDa. Pull-down experiments showed that TANC protein bound PSD-95, SAP97, and Homer via its C-terminal PDZ-binding motif, -ESNV, and fodrin via both its ankyrin repeats and the TPRs together with the coiled-coil domain. TANC also bound the alpha subunit of Ca2+/calmodulin-dependent protein kinase II. An immunoprecipitation study showed TANC association with various postsynaptic proteins, including guanylate kinase-associated protein (GKAP), alpha-internexin, and N-methyl-D-aspartate (NMDA)-type glutamate receptor 2B and AMPA-type glutamate receptor (GluR1) subunits. These results suggest that TANC protein may work as a postsynaptic scaffold component by forming a multiprotein complex with various postsynaptic density proteins.

    The European journal of neuroscience 2005;21;2;339-50

  • 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

  • Topology of Homer 1c and Homer 1a in C2C12 myotubes and transgenic skeletal muscle fibers.

    Volpe P, Sandri C, Bortoloso E, Valle G and Nori A

    Dipartimento di Scienze Biomediche Sperimentali dell'Università di Padova, viale G. Colombo 3, 35121 Paduva, Italy. pompeo.volpe@unipd.it

    mRNA transcripts for Homer 1a and Homer 1c have been detected in skeletal muscle [Biochem. Biophys. Res. Commun. 279 (2000) 348]. Here, the subcellular distribution of recombinant HA1-tagged Homer 1c and HA1-tagged Homer 1a was investigated in C(2)C(12) myotubes and in transgenic skeletal muscle fibers of the adult rat by epifluorescent and confocal microscopy. In C(2)C(12) myotubes, Homer 1a was homogeneously localized in the cytosol and also labeled some nuclei whereas Homer 1c displayed a diffuse reticular/punctuate pattern in the cytosol with scattered punctuate labeling around nuclei; no co-localization was observed with the ryanodine receptor/Ca(2+) release channel (RYR1). The subcellular localization of the Homer 1 isoforms was markedly different in transgenic muscle fibers: Homer 1c was diffusely distributed at the I band and enlightened the Z line, whereas Homer 1a labeled both the I band and the A band with distinct reinforcement of the H line; neither Homer 1c nor Homer 1a co-localized with either calsequestrin or RYR1, two sarcoplasmic reticulum markers. Our findings are discussed in relation to reported effects of Homer 1 isoforms on RYR1 function.

    Biochemical and biophysical research communications 2004;316;3;884-92

  • Homer protein increases activation of Ca2+ sparks in permeabilized skeletal muscle.

    Ward CW, Feng W, Tu J, Pessah IN, Worley PK and Schneider MF

    Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.

    Members of the Homer family of proteins are known to form multimeric complexes capable of cross-linking plasma membrane channels (e.g. metabotropic glutamate receptor) and intracellular Ca2+ release channels (e.g. inositol trisphosphate receptor) in neurons, which potentiates Ca2+ release. Recent work has demonstrated direct interaction of Homer proteins with type 1 and type 2 ryanodine receptor (RyR) isoforms. Moreover, Homer proteins have been shown to modulate RyR-dependent Ca2+ release in isolated channels as well as in whole cell preparations. We now show that long and short forms of Homer H1 (H1c and H1-EVH1) are potent activators of Ca2+ release via RyR in skeletal muscle fibers (e.g. Ca2+ sparks) and potent modulators of ryanodine binding to membranes enriched with RyR, with H1c being significantly more potent than H1-EVH1. Homer did not significantly alter the spatio-temporal properties of the sparks, demonstrating that Homer increases the rate of opening of RyRs, with no change in the overall RyR channel open time and amount of Ca2+ released during a spark. No changes in Ca2+ spark frequency or properties were observed using a full-length H1c with mutation in the EVH1 binding domain (H1c-G89N). One novel finding with each Homer agonist (H1c and H1-EVH1) was that in combination their actions on [3H]ryanodine binding was additive, an effect also observed for these Homer agonists in the Ca2+ spark studies. Finally, in Ca2+ spark studies, excess H1c-G89N prevented the effects of H1c in a dominant negative manner. Taken together our results suggest that the EVH1 domain is critical for the agonist behavior on Ca2+ sparks and ryanodine binding, and that the coiled-coil domain, present in long but not short form Homer, confers an increase in agonist potential apparently through the multimeric association of Homer ligand.

    The Journal of biological chemistry 2004;279;7;5781-7

  • PI3 kinase enhancer-Homer complex couples mGluRI to PI3 kinase, preventing neuronal apoptosis.

    Rong R, Ahn JY, Huang H, Nagata E, Kalman D, Kapp JA, Tu J, Worley PF, Snyder SH and Ye K

    Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Room 145, Whitehead Building, 615 Michael Street, Atlanta, Georgia 30322, USA.

    Phosphoinositide 3 kinase enhancer (PIKE) is a recently identified nuclear GTPase that activates nuclear phosphoinositide 3-kinase (PI3 kinase). We have identified, cloned and characterized a new form of PIKE, designated PIKE-L, which, unlike the nuclear PIKE-S, localizes to both the cytoplasm and the nucleus. We demonstrate physiologic binding of PIKE-L to Homer, an adaptor protein known to link metabotropic glutamate receptors to multiple intracellular targets including the inositol 1,4,5-trisphosphate receptor (IP3R). We show that activation of group I metabotropic glutamate receptors (mGluRIs) enhances formation of an mGluRI-Homer-PIKE-L complex, leading to activation of PI3 kinase activity and prevention of neuronal apoptosis. Our findings indicate that this complex mediates the well-known ability of agonists of mGluRI to prevent neuronal apoptosis.

    Funded by: NINDS NIH HHS: R01 NS045627

    Nature neuroscience 2003;6;11;1153-61

  • Homer binds TRPC family channels and is required for gating of TRPC1 by IP3 receptors.

    Yuan JP, Kiselyov K, Shin DM, Chen J, Shcheynikov N, Kang SH, Dehoff MH, Schwarz MK, Seeburg PH, Muallem S and Worley PF

    Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

    Receptor signaling at the plasma membrane often releases calcium from intracellular stores. For example, inositol triphosphate (IP3) produced by receptor-coupled phospholipase C activates an intracellular store calcium channel, the IP(3)R. Conversely, stores can induce extracellular calcium to enter the cell through plasma membrane channels, too. How this "reverse" coupling works was unclear, but store IP(3)Rs were proposed to bind and regulate plasma membrane TRP cation channels. Here, we demonstrate that the adaptor protein, termed Homer, facilitates a physical association between TRPC1 and the IP(3)R that is required for the TRP channel to respond to signals. The TRPC1-Homer-IP(3)R complex is dynamic and its disassembly parallels TRPC1 channel activation. Homer's action depends on its ability to crosslink and is blocked by the dominant-negative immediate early gene form, H1a. Since H1a is transcriptionally regulated by cellular activity, this mechanism can affect both short and long-term regulation of TRPC1 function.

    Cell 2003;114;6;777-89

  • Vesl/Homer proteins regulate ryanodine receptor type 2 function and intracellular calcium signaling.

    Westhoff JH, Hwang SY, Duncan RS, Ozawa F, Volpe P, Inokuchi K and Koulen P

    Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA.

    Cellular signaling proteins such as metabotropic glutamate receptors, Shank, and different types of ion channels are physically linked by Vesl (VASP/Ena-related gene up-regulated during seizure and LTP)/Homer proteins [Curr. Opin. Neurobiol. 10 (2000) 370; Trends Neurosci. 23 (2000) 80; J. Cell Sci. 113 (2000) 1851]. Vesl/Homer proteins have also been implicated in differentiation and physiological adaptation processes [Nat. Neurosci. 4 (2001) 499; Nature 411 (2001) 962; Biochem. Biophys. Res. Commun. 279 (2000) 348]. Here we provide evidence that a Vesl/Homer subtype, Vesl-1L/Homer-1c (V-1L), reduces the function of the intracellular calcium channel ryanodine receptor type 2 (RyR2). In contrast, Vesl-1S/Homer-1a (V-1S) had no effect on RyR2 function but reversed the effects of V-1L. In live cells, in calcium release studies and in single-channel electrophysiological recordings of RyR2, V-1L reduced RyR2 activity. Important physiological functions and pharmacological properties of RyR2 are preserved in the presence of V-1L. Our findings demonstrate that a protein-protein interaction between V-1L and RyR2 is not only necessary for organizing the structure of intracellular calcium signaling proteins [Curr. Opin. Neurobiol. 10 (2000) 370; Trends Neurosci. 23(2000)80; J. Cell Sci. 113 (2000) 1851; Nat Neurosci. 4 (2001) 499; Nature 411 (2001) 962; Biochem. Biophys. Res. Commun. 279 (2000) 348; Nature 386 (1997) 284], but that V-1L also directly regulates RyR2 channel activity by changing its biophysical properties. Thereby it may control cellular calcium homeostasis. These observations suggest a novel mechanism for the regulation of RyR2 and calcium-dependent cellular functions.

    Cell calcium 2003;34;3;261-9

  • Differential functional interaction of two Vesl/Homer protein isoforms with ryanodine receptor type 1: a novel mechanism for control of intracellular calcium signaling.

    Hwang SY, Wei J, Westhoff JH, Duncan RS, Ozawa F, Volpe P, Inokuchi K and Koulen P

    Department of Pharmacology and Neuroscience, University of North Texas Health Science Center at Fort Worth, Fort Worth, TX 76107, USA.

    Vesl/Homer proteins physically link proteins that mediate cellular signaling [Curr. Opin. Neurobiol. 10 (2000) 370; Trends Neurosci. 23 (2000) 80; J. Cell Sci. 113 (2000) 1851] and thereby influence cellular function [Nat. Neurosci. 4 (2001) 499; Nature 411 (2001) 962]. A previous study reported that Vesl-1L/Homer-1c (V-1L) controls the gain of the intracellular calcium activated calcium channel ryanodine receptor type 1 (RyR1) channel [J. Biol Chem. 277 (2002) 44722]. Here, we show that the function of RyR1 is differentially regulated by two isoforms of Vesl-1/Homer-1, V-1L and Vesl-1S/Homer-1a (V-1S). V-1L increases the activity of RyR1 while important regulatory functions and pharmacological characteristics are preserved. V-1S alone had no effect on RyR1, even though, like V-1L, it is directly bound to the channel. However, V-1S dose-dependently decreased the effects of V-1L on RyR1, providing a novel mechanism for the regulation of intracellular calcium channel activity and calcium homeostasis by changing expression levels of Vesl/Homer proteins.

    Cell calcium 2003;34;2;177-84

  • Mutation screening of the Homer gene family and association analysis in schizophrenia.

    Norton N, Williams HJ, Williams NM, Spurlock G, Zammit S, Jones G, Jones S, Owen R, O'Donovan MC and Owen MJ

    Department of Psychological Medicine, University of Wales College of Medicine, Heath Park, Cardiff, United Kingdom.

    Homer proteins are a group of proteins that regulate group 1 metabotropic glutamate receptor function. As altered glutamate function has been implicated in many neuro psychiatric disorders, particularly schizophrenia, we have screened all three known Homer genes for sequence variation for use under the candidate gene association paradigm. We found seven SNPs, including three in exons. Of these, none was non-synonymous. Allele frequencies of all the detected SNPs were estimated in DNA pools of 368 schizophrenics and 368 controls. Only one (Homer 1 IVS4 + 18A > G) was associated with schizophrenia in this sample, a finding confirmed by individual genotyping (P = 0.01). However, in our extended sample of 680 cases and 671 controls, the evidence for association diminished (P = 0.05). Our results suggest it is unlikely that sequence variants in the Homer genes contribute to the aetiology of schizophrenia, but the variants we identified are plausible candidates for other neuropsychiatric phenotypes.

    Funded by: Medical Research Council: G9309834, G9810900

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2003;120B;1;18-21

  • Homer regulates gain of ryanodine receptor type 1 channel complex.

    Feng W, Tu J, Yang T, Vernon PS, Allen PD, Worley PF and Pessah IN

    Department of Molecular Biosciences, University of California, Davis, California 95616, USA.

    Homer proteins form an adapter system that regulates coupling of group 1 metabotropic glutamate receptors with intracellular inositol trisphosphate receptors and is modified by neuronal activity. Here, we demonstrate that Homer proteins also physically associate with ryanodine receptors type 1 (RyR1) and regulate gating responses to Ca(2+), depolarization, and caffeine. In contrast to the prevailing notion of Homer function, Homer1c (long form) and Homer1-EVH1 (short form) evoke similar changes in RyR activity. The EVH1 domain mediates these actions of Homer and is selectively blocked by a peptide that mimics the Homer ligand. 1B5 dyspedic myotubes expressing RyR1 with a point mutation of a putative Homer-binding domain exhibit significantly reduced (approximately 33%) amplitude in their responses to K(+) depolarization compared with cells expressing wild type protein. These results reveal that in addition to its known role as an adapter protein, Homer is a direct modulator of Ca(2+) release gain. Homer is the first example of an "adapter" that also modifies signaling properties of its target protein. The present work reveals a novel mechanism by which Homer directly modulates the function of its target protein RyR1 and excitation-contraction coupling in skeletal myotubes. This form of regulation may be important in other cell types that express Homer and RyR1.

    Funded by: NIAMS NIH HHS: AR17605; NIDA NIH HHS: DA10309; NIEHS NIH HHS: ES10173, ES11269; NIMH NIH HHS: MH01153

    The Journal of biological chemistry 2002;277;47;44722-30

  • Expressed sequence tag analysis of human RPE/choroid for the NEIBank Project: over 6000 non-redundant transcripts, novel genes and splice variants.

    Wistow G, Bernstein SL, Wyatt MK, Fariss RN, Behal A, Touchman JW, Bouffard G, Smith D and Peterson K

    Section on Molecular Structure and Function, National Eye Institute, National Institutes of Health, Bethesda, MD 20892-2740, USA. graeme@helix.nih.gov

    Purpose: The retinal pigment epithelium (RPE) and choroid comprise a functional unit of the eye that is essential to normal retinal health and function. Here we describe expressed sequence tag (EST) analysis of human RPE/choroid as part of a project for ocular bioinformatics.

    Methods: A cDNA library (cs) was made from human RPE/choroid and sequenced. Data were analyzed and assembled using the program GRIST (GRouping and Identification of Sequence Tags). Complete sequencing, Northern and Western blots, RH mapping, peptide antibody synthesis and immunofluorescence (IF) have been used to examine expression patterns and genome location for selected transcripts and proteins.

    Results: Ten thousand individual sequence reads yield over 6300 unique gene clusters of which almost half have no matches with named genes. One of the most abundant transcripts is from a gene (named "alpha") that maps to the BBS1 region of chromosome 11. A number of tissue preferred transcripts are common to both RPE/choroid and iris. These include oculoglycan/opticin, for which an alternative splice form is detected in RPE/choroid, and "oculospanin" (Ocsp), a novel tetraspanin that maps to chromosome 17q. Antiserum to Ocsp detects expression in RPE, iris, ciliary body, and retinal ganglion cells by IF. A newly identified gene for a zinc-finger protein (TIRC) maps to 19q13.4. Variant transcripts of several genes were also detected. Most notably, the predominant form of Bestrophin represented in cs contains a longer open reading frame as a result of splice junction skipping.

    Conclusions: The unamplified cs library gives a view of the transcriptional repertoire of the adult RPE/choroid. A large number of potentially novel genes and splice forms and candidates for genetic diseases are revealed. Clones from this collection are being included in a large, nonredundant set for cDNA microarray construction.

    Molecular vision 2002;8;205-20

  • Parkin and CASK/LIN-2 associate via a PDZ-mediated interaction and are co-localized in lipid rafts and postsynaptic densities in brain.

    Fallon L, Moreau F, Croft BG, Labib N, Gu WJ and Fon EA

    Centre for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada.

    Mutations in the gene encoding parkin cause an autosomal recessive juvenile-onset form of Parkinson's disease. Parkin functions as a RING-type E3 ubiquitin-ligase, coordinating the transfer of ubiquitin to substrate proteins and thereby targeting them for degradation by the proteasome. We now report that the extreme C terminus of parkin, which is selectively truncated by a Parkinson's disease-causing mutation, functions as a class II PDZ-binding motif that binds CASK, the mammalian homolog of Caenorhabditis elegans Lin-2, but not other PDZ proteins in brain extracts. Importantly, parkin co-localizes with CASK at synapses in cultured cortical neurons as well as in postsynaptic densities and lipid rafts in brain. Further, parkin associates not only with CASK but also with other postsynaptic proteins in the N-methyl d-aspartate (NMDA) receptor-signaling complex, in rat brain in vivo. Finally, despite exhibiting E2-dependent ubiquitin ligase activity, rat brain parkin does not ubiquitinate CASK, suggesting that CASK may function in targeting or scaffolding parkin within the postsynaptic complex rather than as a direct substrate for parkin-mediated ubiquitination. These data implicate for the first time a PDZ-mediated interaction between parkin and CASK in neurodegeneration and possibly in ubiquitination of proteins involved in synaptic transmission and plasticity.

    The Journal of biological chemistry 2002;277;1;486-91

  • Agonist-independent activation of metabotropic glutamate receptors by the intracellular protein Homer.

    Ango F, Prézeau L, Muller T, Tu JC, Xiao B, Worley PF, Pin JP, Bockaert J and Fagni L

    CNRS-UPR 9023, CCIPE, 141 Rue de la Cardonille, 34000 Montpellier, France.

    G-protein-coupled receptors (GPCRs) transduce signals from extracellular transmitters to the inside of the cell by activating G proteins. Mutation and overexpression of these receptors have revealed that they can reach their active state even in the absence of agonist, as a result of a natural shift in the equilibrium between their inactive and active conformations. Such agonist-independent (constitutive) activity has been observed for the glutamate GPCRs (the metabotropic glutamate receptors mGluR1a and mGluR5) when they are overexpressed in heterologous cells. Here we show that in neurons, the constitutive activity of these receptors is controlled by Homer proteins, which bind directly to the receptors' carboxy-terminal intracellular domains. Disruption of this interaction by mutagenesis or antisense strategies, or expression of endogenous Homer1a (H1a), induces constitutive activity in mGluR1a or mGluR5. Our results show that these glutamate GPCRs can be directly activated by intracellular proteins as well as by agonists.

    Nature 2001;411;6840;962-5

  • Interaction of Vesl-1L/Homer 1c with syntaxin 13.

    Minakami R, Kato A and Sugiyama H

    School of Health Sciences, Kyushu University, Fukuoka, Japan.

    Vesl-1S/Homer 1a, reported originally as Vesl/Homer, was isolated as a synaptic plasticity-regulated gene. The expression of Vesl-1S/Homer 1a is regulated during long-term potentiation in the hippocampus. Vesl-1L/Homer 1c, which appears to be formed by a splicing event, shares the N-terminus with Vesl-1S/Homer 1a and also contains additional amino acids at the C-terminus. The short form and the long form of the family members both interact with group 1 metabotropic glutamate receptors (mGluRs). We herein report the identification of syntaxin 13 as a molecule that interacts with Vesl-1L using yeast two-hybrid screening. Syntaxin 13 is a member of the syntaxin family and is regarded as soluble N-ethylmaleimide-sensitive attachment proteins receptors (SNAREs) in the endosomal membranes. The interaction of Vesl-1L and syntaxin 13 was biochemically confirmed by in vitro binding assays. The coexpression of the two proteins in the transfected cells resulted in a colocalization in the intracellular vesicle-like structures. We thus propose that the association of Vesl-1L with syntaxin 13 plays a role in the translocation of Vesl-1L to the intracellular organelles.

    Biochemical and biophysical research communications 2000;272;2;466-71

  • Homer: a link between neural activity and glutamate receptor function.

    Xiao B, Tu JC and Worley PF

    Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

    The proteins of the Homer family bind to proline-rich sequences in group I metabotropic glutamate receptors, inositol trisphosphate receptors, ryanodine receptors, and Shank family proteins. Homer proteins also self associate and function as adaptors to couple interacting proteins. Recent observations indicate a role for Homer complexes in signal transduction, synaptogenesis and receptor trafficking.

    Current opinion in neurobiology 2000;10;3;370-4

  • Homer 1b regulates the trafficking of group I metabotropic glutamate receptors.

    Roche KW, Tu JC, Petralia RS, Xiao B, Wenthold RJ and Worley PF

    Laboratory of Neurochemistry, NIDCD, National Institutes of Health, Bethesda, Maryland 20892, USA. rochek@nidcd.nih.gov

    The molecular basis for glutamate receptor trafficking to the plasma membrane is not understood. In the present study, we demonstrate that Homer 1b (H1b), a constitutively expressed splice form of the immediate early gene product Homer (now termed Homer 1a) regulates the trafficking and surface expression of group I metabotropic glutamate receptors. H1b inhibits surface expression of the metabotropic glutamate receptor mGluR5 in heterologous cells, causing mGluR5 to be retained in the endoplasmic reticulum (ER). In contrast, mGluR5 alone or mGluR5 coexpressed with Homer 1a successfully travels through the secretory pathway to the plasma membrane. In addition, point mutations that disrupt mGluR5 binding to H1b eliminate ER retention of mGluR5, demonstrating that H1b affects metabotropic receptor localization via a direct protein-protein interaction. Electron microscopic analysis reveals that the group I metabotropic receptor mGluR1alpha is significantly enriched in the ER of Purkinje cells, suggesting that a similar mechanism may exist in vivo. Because H1b is found in dendritic spines of neurons, local retention of metabotropic receptors within dendritic ER provides a potential mechanism for regulating synapse-specific expression of group I metabotropic glutamate receptors.

    The Journal of biological chemistry 1999;274;36;25953-7

  • Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins.

    Tu JC, Xiao B, Naisbitt S, Yuan JP, Petralia RS, Brakeman P, Doan A, Aakalu VK, Lanahan AA, Sheng M and Worley PF

    Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

    Shank is a recently described family of postsynaptic proteins that function as part of the NMDA receptor-associated PSD-95 complex (Naisbitt et al., 1999 [this issue of Neuron]). Here, we report that Shank proteins also bind to Homer. Homer proteins form multivalent complexes that bind proline-rich motifs in group 1 metabotropic glutamate receptors and inositol trisphosphate receptors, thereby coupling these receptors in a signaling complex. A single Homer-binding site is identified in Shank, and Shank and Homer coimmunoprecipitate from brain and colocalize at postsynaptic densities. Moreover, Shank clusters mGluR5 in heterologous cells in the presence of Homer and mediates the coclustering of Homer with PSD-95/GKAP. Thus, Shank may cross-link Homer and PSD-95 complexes in the PSD and play a role in the signaling mechanisms of both mGluRs and NMDA receptors.

    Funded by: NIDA NIH HHS: DA10309, DA11742; NIMH NIH HHS: KO2 MH01152; ...

    Neuron 1999;23;3;583-92

  • Homer binds a novel proline-rich motif and links group 1 metabotropic glutamate receptors with IP3 receptors.

    Tu JC, Xiao B, Yuan JP, Lanahan AA, Leoffert K, Li M, Linden DJ and Worley PF

    Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

    Group I metabotropic glutamate receptors (mGluRs) activate PI turnover and thereby trigger intracellular calcium release. Previously, we demonstrated that mGluRs form natural complexes with members of a family of Homer-related synaptic proteins. Here, we present evidence that Homer proteins form a physical tether linking mGluRs with the inositol trisphosphate receptors (IP3R). A novel proline-rich "Homer ligand" (PPXXFr) is identified in group 1 mGluRs and IP3R, and these receptors coimmunoprecipitate as a complex with Homer from brain. Expression of the IEG form of Homer, which lacks the ability to cross-link, modulates mGluR-induced intracellular calcium release. These studies identify a novel mechanism in calcium signaling and provide evidence that an IEG, whose expression is driven by synaptic activity, can directly modify a specific synaptic function.

    Funded by: NIDA NIH HHS: DA 10309, DA 11742; NIMH NIH HHS: KO2 MH01152; ...

    Neuron 1998;21;4;717-26

  • Homer regulates the association of group 1 metabotropic glutamate receptors with multivalent complexes of homer-related, synaptic proteins.

    Xiao B, Tu JC, Petralia RS, Yuan JP, Doan A, Breder CD, Ruggiero A, Lanahan AA, Wenthold RJ and Worley PF

    Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

    Homer is a neuronal immediate early gene (IEG) that is enriched at excitatory synapses and binds group 1 metabotropic glutamate receptors (mGluRs). Here, we characterize a family of Homer-related proteins derived from three distinct genes. Like Homer IEG (now termed Homer 1a), all new members bind group 1 mGluRs. In contrast to Homer 1a, new members are constitutively expressed and encode a C-terminal coiled-coil (CC) domain that mediates self-multimerization. CC-Homers form natural complexes that cross-link mGluRs and are enriched at the postsynaptic density. Homer 1a does not multimerize and blocks the association of mGluRs with CC-Homer complexes. These observations support a model in which the dynamic expression of Homer 1a competes with constitutively expressed CC-Homers to modify synaptic mGluR properties.

    Funded by: NIDA NIH HHS: DA10309, DA11742; NIMH NIH HHS: KO2 MH01152; ...

    Neuron 1998;21;4;707-16

  • Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library.

    Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A and Sugano S

    International and Interdisciplinary Studies, The University of Tokyo, Japan.

    Using 'oligo-capped' mRNA [Maruyama, K., Sugano, S., 1994. Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. Gene 138, 171-174], whose cap structure was replaced by a synthetic oligonucleotide, we constructed two types of cDNA library. One is a 'full length-enriched cDNA library' which has a high content of full-length cDNA clones and the other is a '5'-end-enriched cDNA library', which has a high content of cDNA clones with their mRNA start sites. The 5'-end-enriched library was constructed especially for isolating the mRNA start sites of long mRNAs. In order to characterize these libraries, we performed one-pass sequencing of randomly selected cDNA clones from both libraries (84 clones for the full length-enriched cDNA library and 159 clones for the 5'-end-enriched cDNA library). The cDNA clones of the polypeptide chain elongation factor 1 alpha were most frequently (nine clones) isolated, and more than 80% of them (eight clones) contained the mRNA start site of the gene. Furthermore, about 80% of the cDNA clones of both libraries whose sequence matched with known genes had the known 5' ends or sequences upstream of the known 5' ends (28 out of 35 for the full length-enriched library and 51 out of 62 for the 5'-end-enriched library). The longest full-length clone of the full length-enriched cDNA library was about 3300 bp (among 28 clones). In contrast, seven clones (out of the 51 clones with the mRNA start sites) from the 5'-end-enriched cDNA library came from mRNAs whose length is more than 3500 bp. These cDNA libraries may be useful for generating 5' ESTs with the information of the mRNA start sites that are now scarce in the EST database.

    Gene 1997;200;1-2;149-56

  • Homer: a protein that selectively binds metabotropic glutamate receptors.

    Brakeman PR, Lanahan AA, O'Brien R, Roche K, Barnes CA, Huganir RL and Worley PF

    Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

    Spatial localization and clustering of membrane proteins is critical to neuronal development and synaptic plasticity. Recent studies have identified a family of proteins, the PDZ proteins, that contain modular PDZ domains and interact with synaptic ionotropic glutamate receptors and ion channels. PDZ proteins are thought to have a role in defining the cellular distribution of the proteins that interact with them. Here we report a novel dendritic protein, Homer, that contains a single, PDZ-like domain and binds specifically to the carboxy terminus of phosphoinositide-linked metabotropic glutamate receptors. Homer is highly divergent from known PDZ proteins and seems to represent a novel family. The Homer gene is also distinct from members of the PDZ family in that its expression is regulated as an immediate early gene and is dynamically responsive to physiological synaptic activity, particularly during cortical development. This dynamic transcriptional control suggests that Homer mediates a novel cellular mechanism that regulates metabotropic glutamate signalling.

    Nature 1997;386;6622;284-8

  • Generation and analysis of 280,000 human expressed sequence tags.

    Hillier LD, Lennon G, Becker M, Bonaldo MF, Chiapelli B, Chissoe S, Dietrich N, DuBuque T, Favello A, Gish W, Hawkins M, Hultman M, Kucaba T, Lacy M, Le M, Le N, Mardis E, Moore B, Morris M, Parsons J, Prange C, Rifkin L, Rohlfing T, Schellenberg K, Bento Soares M, Tan F, Thierry-Meg J, Trevaskis E, Underwood K, Wohldman P, Waterston R, Wilson R and Marra M

    Genome Sequencing Center, Washington University School of Medicine, St. Louis, Missouri 63108, USA. lhillier@watson.wustl.edu

    We report the generation of 319,311 single-pass sequencing reactions (known as expressed sequence tags, or ESTs) obtained from the 5' and 3' ends of 194,031 human cDNA clones. Our goal has been to obtain tag sequences from many different genes and to deposit these in the publicly accessible Data Base for Expressed Sequence Tags. Highly efficient automatic screening of the data allows deposition of the annotated sequences without delay. Sequences have been generated from 26 oligo(dT) primed directionally cloned libraries, of which 18 were normalized. The libraries were constructed using mRNA isolated from 17 different tissues representing three developmental states. Comparisons of a subset of our data with nonredundant human mRNA and protein data bases show that the ESTs represent many known sequences and contain many that are novel. Analysis of protein families using Hidden Markov Models confirms this observation and supports the contention that although normalization reduces significantly the relative abundance of redundant cDNA clones, it does not result in the complete removal of members of gene families.

    Genome research 1996;6;9;807-28

  • Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides.

    Maruyama K and Sugano S

    Institute of Medical Science, University of Tokyo, Japan.

    We have devised a method to replace the cap structure of a mRNA with an oligoribonucleotide (r-oligo) to label the 5' end of eukaryotic mRNAs. The method consists of removing the cap with tobacco acid pyrophosphatase (TAP) and ligating r-oligos to decapped mRNAs with T4 RNA ligase. This reaction was made cap-specific by removing 5'-phosphates of non-capped RNAs with alkaline phosphatase prior to TAP treatment. Unlike the conventional methods that label the 5' end of cDNAs, this method specifically labels the capped end of the mRNAs with a synthetic r-oligo prior to first-strand cDNA synthesis. The 5' end of the mRNA was identified quite simply by reverse transcription-polymerase chain reaction (RT-PCR).

    Gene 1994;138;1-2;171-4

Gene lists (9)

Gene List Source Species Name Description Gene count
L00000009 G2C Homo sapiens Human PSD Human orthologues of mouse PSD adapted from Collins et al (2006) 1080
L00000013 G2C Homo sapiens Human mGluR5 Human orthologues of mouse mGluR5 complex adapted from Collins et al (2006) 52
L00000015 G2C Homo sapiens Human NRC Human orthologues of mouse NRC adapted from Collins et al (2006) 186
L00000016 G2C Homo sapiens Human PSP Human orthologues of mouse PSP adapted from Collins et al (2006) 1121
L00000033 G2C Homo sapiens Pocklington H2 Human orthologues of cluster 2 (mouse) from Pocklington et al (2006) 13
L00000059 G2C Homo sapiens BAYES-COLLINS-HUMAN-PSD-CONSENSUS Human cortex PSD consensus 748
L00000061 G2C Homo sapiens BAYES-COLLINS-MOUSE-PSD-CONSENSUS Mouse cortex PSD consensus (ortho) 984
L00000069 G2C Homo sapiens BAYES-COLLINS-HUMAN-PSD-FULL Human cortex biopsy PSD full list 1461
L00000071 G2C Homo sapiens BAYES-COLLINS-MOUSE-PSD-FULL Mouse cortex PSD full list (ortho) 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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