G2Cdb::Gene report

Gene id
G00000007
Gene symbol
Dlg3 (MGI)
Species
Mus musculus
Description
discs, large homolog 3 (Drosophila)
Orthologue
G00000032 (Homo sapiens)

Databases (10)

Curated Gene
OTTMUSG00000016499 (Vega mouse gene)
Gene
ENSMUSG00000000881 (Ensembl mouse gene)
53310 (Entrez Gene)
13 (G2Cdb plasticity & disease)
Gene Expression
MGI:1888986 (Allen Brain Atlas)
g02349 (BGEM)
dlg3 (gensat)
Literature
300189 (OMIM)
Marker Symbol
MGI:1888986 (MGI)
Protein Sequence
P70175 (UniProt)

Synonyms (3)

  • DLG3
  • Dlgh3
  • SAP102

Alleles (2)

Allele Name Type Description Literature
A00000028 SAP102 ko knockout Dlg3 (SAP102) knockout (17344405)
  • Synapse-associated protein 102/dlgh3 couples the NMDA receptor to specific plasticity pathways and learning strategies.

    Cuthbert PC, Stanford LE, Coba MP, Ainge JA, Fink AE, Opazo P, Delgado JY, Komiyama NH, O'Dell TJ and Grant SG

    Wellcome Trust Sanger Institute, Cambridge CB10 1SA, United Kingdom.

    Understanding the mechanisms whereby information encoded within patterns of action potentials is deciphered by neurons is central to cognitive psychology. The multiprotein complexes formed by NMDA receptors linked to synaptic membrane-associated guanylate kinase (MAGUK) proteins including synapse-associated protein 102 (SAP102) and other associated proteins are instrumental in these processes. Although humans with mutations in SAP102 show mental retardation, the physiological and biochemical mechanisms involved are unknown. Using SAP102 knock-out mice, we found specific impairments in synaptic plasticity induced by selective frequencies of stimulation that also required extracellular signal-regulated kinase signaling. This was paralleled by inflexibility and impairment in spatial learning. Improvement in spatial learning performance occurred with extra training despite continued use of a suboptimal search strategy, and, in a separate nonspatial task, the mutants again deployed a different strategy. Double-mutant analysis of postsynaptic density-95 and SAP102 mutants indicate overlapping and specific functions of the two MAGUKs. These in vivo data support the model that specific MAGUK proteins couple the NMDA receptor to distinct downstream signaling pathways. This provides a mechanism for discriminating patterns of synaptic activity that lead to long-lasting changes in synaptic strength as well as distinct aspects of cognition in the mammalian nervous system.

    Funded by: NIMH NIH HHS: R01 MH060919, R01 MH060919-10; Wellcome Trust: 077155

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2007;27;10;2673-82

Literature (24)

Pubmed - g2c

  • Targeted tandem affinity purification of PSD-95 recovers core postsynaptic complexes and schizophrenia susceptibility proteins.

    Fernández E, Collins MO, Uren RT, Kopanitsa MV, Komiyama NH, Croning MD, Zografos L, Armstrong JD, Choudhary JS and Grant SG

    Genes to Cognition Programme, The Wellcome Trust Sanger Institute, Cambridge, UK.

    The molecular complexity of mammalian proteomes demands new methods for mapping the organization of multiprotein complexes. Here, we combine mouse genetics and proteomics to characterize synapse protein complexes and interaction networks. New tandem affinity purification (TAP) tags were fused to the carboxyl terminus of PSD-95 using gene targeting in mice. Homozygous mice showed no detectable abnormalities in PSD-95 expression, subcellular localization or synaptic electrophysiological function. Analysis of multiprotein complexes purified under native conditions by mass spectrometry defined known and new interactors: 118 proteins comprising crucial functional components of synapses, including glutamate receptors, K+ channels, scaffolding and signaling proteins, were recovered. Network clustering of protein interactions generated five connected clusters, with two clusters containing all the major ionotropic glutamate receptors and one cluster with voltage-dependent K+ channels. Annotation of clusters with human disease associations revealed that multiple disorders map to the network, with a significant correlation of schizophrenia within the glutamate receptor clusters. This targeted TAP tagging strategy is generally applicable to mammalian proteomics and systems biology approaches to disease.

    Funded by: Wellcome Trust

    Molecular systems biology 2009;5;269

  • Clustered gene expression changes flank targeted gene loci in knockout mice.

    Valor LM and Grant SG

    Genes to Cognition Programme, The Wellcome Trust Sanger Institute, Cambridge, United Kingdom.

    Background: Gene expression profiling using microarrays is a powerful technology widely used to study regulatory networks. Profiling of mRNA levels in mutant organisms has the potential to identify genes regulated by the mutated protein.

    Using tissues from multiple lines of knockout mice we have examined genome-wide changes in gene expression. We report that a significant proportion of changed genes were found near the targeted gene.

    The apparent clustering of these genes was explained by the presence of flanking DNA from the parental ES cell. We provide recommendations for the analysis and reporting of microarray data from knockout mice.

    Funded by: Wellcome Trust

    PloS one 2007;2;12;e1303

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

  • Phenotypic annotation of the mouse X chromosome.

    Cox BJ, Vollmer M, Tamplin O, Lu M, Biechele S, Gertsenstein M, van Campenhout C, Floss T, Kühn R, Wurst W, Lickert H and Rossant J

    Program in Developmental and Stem Cell Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario M5G 1L7, Canada.

    Mutational screens are an effective means used in the functional annotation of a genome. We present a method for a mutational screen of the mouse X chromosome using gene trap technologies. This method has the potential to screen all of the genes on the X chromosome without establishing mutant animals, as all gene-trapped embryonic stem (ES) cell lines are hemizygous null for mutations on the X chromosome. Based on this method, embryonic morphological phenotypes and expression patterns for 58 genes were assessed, approximately 10% of all human and mouse syntenic genes on the X chromosome. Of these, 17 are novel embryonic lethal mutations and nine are mutant mouse models of genes associated with genetic disease in humans, including BCOR and PORCN. The rate of lethal mutations is similar to previous mutagenic screens of the autosomes. Interestingly, some genes associated with X-linked mental retardation (XLMR) in humans show lethal phenotypes in mice, suggesting that null mutations cannot be responsible for all cases of XLMR. The entire data set is available via the publicly accessible website (http://xlinkedgenes.ibme.utoronto.ca/).

    Genome research 2010;20;8;1154-64

  • Neto1 is a novel CUB-domain NMDA receptor-interacting protein required for synaptic plasticity and learning.

    Ng D, Pitcher GM, Szilard RK, Sertié A, Kanisek M, Clapcote SJ, Lipina T, Kalia LV, Joo D, McKerlie C, Cortez M, Roder JC, Salter MW and McInnes RR

    Program in Developmental Biology, The Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.

    The N-methyl-D-aspartate receptor (NMDAR), a major excitatory ligand-gated ion channel in the central nervous system (CNS), is a principal mediator of synaptic plasticity. Here we report that neuropilin tolloid-like 1 (Neto1), a complement C1r/C1s, Uegf, Bmp1 (CUB) domain-containing transmembrane protein, is a novel component of the NMDAR complex critical for maintaining the abundance of NR2A-containing NMDARs in the postsynaptic density. Neto1-null mice have depressed long-term potentiation (LTP) at Schaffer collateral-CA1 synapses, with the subunit dependency of LTP induction switching from the normal predominance of NR2A- to NR2B-NMDARs. NMDAR-dependent spatial learning and memory is depressed in Neto1-null mice, indicating that Neto1 regulates NMDA receptor-dependent synaptic plasticity and cognition. Remarkably, we also found that the deficits in LTP, learning, and memory in Neto1-null mice were rescued by the ampakine CX546 at doses without effect in wild-type. Together, our results establish the principle that auxiliary proteins are required for the normal abundance of NMDAR subunits at synapses, and demonstrate that an inherited learning defect can be rescued pharmacologically, a finding with therapeutic implications for humans.

    Funded by: Howard Hughes Medical Institute

    PLoS biology 2009;7;2;e41

  • Differential trafficking of AMPA and NMDA receptors by SAP102 and PSD-95 underlies synapse development.

    Elias GM, Elias LA, Apostolides PF, Kriegstein AR and Nicoll RA

    Neuroscience Graduate Program, University of California, San Francisco, CA 94143, USA.

    The development of glutamatergic synapses involves changes in the number and type of receptors present at the postsynaptic density. To elucidate molecular mechanisms underlying these changes, we combine in utero electroporation of constructs that alter the molecular composition of developing synapses with dual whole-cell electrophysiology to examine synaptic transmission during two distinct developmental stages. We find that SAP102 mediates synaptic trafficking of AMPA and NMDA receptors during synaptogenesis. Surprisingly, after synaptogenesis, PSD-95 assumes the functions of SAP102 and is necessary for two aspects of synapse maturation: the developmental increase in AMPA receptor transmission and replacement of NR2B-NMDARs with NR2A-NMDARs. In PSD-95/PSD-93 double-KO mice, the maturational replacement of NR2B- with NR2A-NMDARs fails to occur, and PSD-95 expression fully rescues this deficit. This study demonstrates that SAP102 and PSD-95 regulate the synaptic trafficking of distinct glutamate receptor subtypes at different developmental stages, thereby playing necessary roles in excitatory synapse development.

    Funded by: NIMH NIH HHS: R37 MH038256

    Proceedings of the National Academy of Sciences of the United States of America 2008;105;52;20953-8

  • Cloning and characterization of E-dlg, a novel splice variant of mouse homologue of the Drosophila discs large tumor suppressor binds preferentially to SAP102.

    Mao P, Tao YX, Fukaya M, Tao F, Li D, Watanabe M and Johns RA

    Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. maop@ohsu.edu

    Membrane-associated guanylate kinases (MAGUKs) act as scaffolds to coordinate signaling events through their multiple domains at the plasma membrane. The MAGUK SH3 domain is noncanonical and its function remains unclear. To identify potential binding partners of MAGUK SH3, the synapse-associated protein 102 (SAP102) SH3 domain was used as bait in a yeast two-hybrid screen of a mouse embryonic cDNA library. A mouse homologue of the Drosophila discs large tumor suppressor (Dlg, also known as SAP97) bound preferentially to SAP102 SH3. The 4347bp cDNA sequence encoded an 893 amino acid protein with 94% identity to mouse SAP97. A deleted region (33-aa) strongly suggests this is a novel splice variant, which we call Embryonic-dlg/SAP97 (E-dlg). The interaction of SAP102 and E-dlg was confirmed in mammalian cells. E-dlg can also bind to potassium channel Kv1.4 in a pull-down assay. E-dlg was highly expressed in embryonic and some adult mouse tissues, such as brain, kidney, and ovary. Furthermore, in situ hybridization showed that E-dlg was mostly expressed in olfactory bulb and cerebellum.

    Funded by: NIGMS NIH HHS: GM49111, R01 GM049111, R01 GM049111-14, R01 GM049111-15

    IUBMB life 2008;60;10;684-92

  • Genes, plasticity and mental retardation.

    Vaillend C, Poirier R and Laroche S

    Centre National de la Recherche Scientifique, Laboratoire de Neurobiologie de l'Apprentissage, de la Mémoire et de la Communication, UMR 8620, Orsay, France. cyrille.vaillend@u-psud.fr

    Functional and structural plasticity is a fundamental property of the brain involved in diverse processes ranging from brain construction and repair to storage of experiences during lifetime. Our current understanding of different forms of brain plasticity mechanisms has advanced tremendously in the last decades, benefiting from studies of development and memory storage in adulthood and from investigations of diverse diseased conditions. In this review, we focus on the role of mental retardation (MR) genes and show how this developing area of research can enrich our knowledge of the cellular and molecular mechanisms of brain plasticity and cognitive functions, and of the dysfunctional mechanisms underlying MR. We describe two main groups of MR genes; those leading to dysfunctional neurodevelopmental programs and brain malformations, and those which rely on alterations in molecular mechanisms underlying synaptic organization and plasticity. We first explore the role of MR genes in key mechanisms of neurogenesis and neuronal migration during development and in the adult, such as actin and microtubule-cytoskeletal dynamics and signal transduction. We then define the contribution of MR genes to forms of activity-dependent synaptic modifications, such as those involved in molecular organization of the synapse, intracellular signaling regulating gene programs and neuronal cytoskeleton to control network remodeling. We trace the characteristics of MR genes playing key roles in many forms of brain plasticity mechanisms, and highlight specific MR genes that endorse distinct roles in different cell types or brain regions, and at various times of a brain lifetime.

    Behavioural brain research 2008;192;1;88-105

  • A novel view of the transcriptome revealed from gene trapping in mouse embryonic stem cells.

    Roma G, Cobellis G, Claudiani P, Maione F, Cruz P, Tripoli G, Sardiello M, Peluso I and Stupka E

    Telethon Institute of Genetics and Medicine, 80131 Napoli, Italy.

    Embryonic stem (ES) cells are pluripotent cell lines with the capacity of self-renewal and the ability to differentiate into specific cell types. We performed the first genome-wide analysis of the mouse ES cell transcriptome using approximately 250,000 gene trap sequence tags deposited in public databases. We unveiled >8000 novel transcripts, mostly non-coding, and >1000 novel alternative and often tissue-specific exons of known genes. Experimental verification of the expression of these genes and exons by RT-PCR yielded a 70% validation rate. A novel non-coding transcript within the set studied showed a highly specific pattern of expression by in situ hybridization. Our analysis also shows that the genome presents gene trapping hotspots, which correspond to 383 known and 87 novel genes. These "hypertrapped" genes show minimal overlap with previously published expression profiles of ES cells; however, we prove by real-time PCR that they are highly expressed in this cell type, thus potentially contributing to the phenotype of ES cells. Although gene trapping was initially devised as an insertional mutagenesis technique, our study demonstrates its impact on the discovery of a substantial and unprecedented portion of the transcriptome.

    Funded by: Telethon: TGM03P18, TGM06S01

    Genome research 2007;17;7;1051-60

  • Synapse-associated protein 102/dlgh3 couples the NMDA receptor to specific plasticity pathways and learning strategies.

    Cuthbert PC, Stanford LE, Coba MP, Ainge JA, Fink AE, Opazo P, Delgado JY, Komiyama NH, O'Dell TJ and Grant SG

    Wellcome Trust Sanger Institute, Cambridge CB10 1SA, United Kingdom.

    Understanding the mechanisms whereby information encoded within patterns of action potentials is deciphered by neurons is central to cognitive psychology. The multiprotein complexes formed by NMDA receptors linked to synaptic membrane-associated guanylate kinase (MAGUK) proteins including synapse-associated protein 102 (SAP102) and other associated proteins are instrumental in these processes. Although humans with mutations in SAP102 show mental retardation, the physiological and biochemical mechanisms involved are unknown. Using SAP102 knock-out mice, we found specific impairments in synaptic plasticity induced by selective frequencies of stimulation that also required extracellular signal-regulated kinase signaling. This was paralleled by inflexibility and impairment in spatial learning. Improvement in spatial learning performance occurred with extra training despite continued use of a suboptimal search strategy, and, in a separate nonspatial task, the mutants again deployed a different strategy. Double-mutant analysis of postsynaptic density-95 and SAP102 mutants indicate overlapping and specific functions of the two MAGUKs. These in vivo data support the model that specific MAGUK proteins couple the NMDA receptor to distinct downstream signaling pathways. This provides a mechanism for discriminating patterns of synaptic activity that lead to long-lasting changes in synaptic strength as well as distinct aspects of cognition in the mammalian nervous system.

    Funded by: NIMH NIH HHS: R01 MH060919, R01 MH060919-10; Wellcome Trust: 077155

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2007;27;10;2673-82

  • Lhx3, a LIM domain transcription factor, is regulated by Pou4f3 in the auditory but not in the vestibular system.

    Hertzano R, Dror AA, Montcouquiol M, Ahmed ZM, Ellsworth B, Camper S, Friedman TB, Kelley MW and Avraham KB

    Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.

    A dominant mutation of the gene encoding the POU4F3 transcription factor underlies human non-syndromic progressive hearing loss DFNA15. Using oligonucleotide microarrays to generate expression profiles of inner ears of Pou4f3(ddl/ddl) mutant and wild-type mice, we have identified and validated Lhx3, a LIM domain transcription factor, as an in vivo target gene regulated by Pou4f3. Lhx3 is a hair cell-specific gene expressed in all hair cells of the auditory and vestibular system as early as embryonic day 16. The level of Lhx3 mRNA is greatly reduced in the inner ears of embryonic Pou4f3 mutant mice. Our data also show that the expression of Lhx3 is regulated differently in auditory and vestibular hair cells. This is the first example of a hair cell-specific gene expressed both in auditory and in vestibular hair cells, with differential regulation of expression in these two closely related systems.

    Funded by: NIDCD NIH HHS: R01 DC005641, R01DC041557

    The European journal of neuroscience 2007;25;4;999-1005

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

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

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

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

    PLoS biology 2006;4;4;e86

  • A novel family of adhesion-like molecules that interacts with the NMDA receptor.

    Wang CY, Chang K, Petralia RS, Wang YX, Seabold GK and Wenthold RJ

    Laboratory of Neurochemistry, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland 20892-8027, USA.

    We have identified a novel family of synaptic adhesion-like molecules (SALMs). The family members, SALM1-SALM4, have a single transmembrane (TM) domain and contain extracellular leucine-rich repeats, an Ig C2 type domain, a fibronectin type III domain, and an intracellular postsynaptic density-95 (PSD-95)/Discs large/zona occludens-1 (PDZ) binding domain, which is present on all members except SALM4. SALM1 interacts with PSD-95, synapse-associated protein 102 (SAP102), and SAP97 based on coimmunoprecipitation of detergent-solubilized brain. Distribution studies show that SALM1 is present in synaptic membrane and postsynaptic density fractions but is also distributed in axons and dendrites. Transfection of hippocampal neurons for 4 d in vitro (DIV) with SALM1 more than doubles the dendritic lengths of neurons after 48 h, whereas transfection of neurons 14 DIV has no significant effect on neurite outgrowth. Overexpression of SALM1 in 14 DIV neurons recruits NMDA receptors (NR) and PSD-95 to dendritic puncta. This effect is dependent on the PDZ-binding domain of SALM1. SALM1 also enhances surface expression of transfected NR2A subunit. Immunoprecipitation of detergent-solubilized brain membranes with anti-SALM1 antibodies shows coimmunoprecipitation of NR1 and NR2 subunits. After transfection of heterologous cells with NR1 and NR2 cDNAs, through coimmunoprecipitation analyses, we find that SALM1 also interacts with the NMDA receptor NR1 subunit through its extracellular or TM1 domains.

    Funded by: Intramural NIH HHS

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2006;26;8;2174-83

  • Characterization of an exchangeable gene trap using pU-17 carrying a stop codon-beta geo cassette.

    Taniwaki T, Haruna K, Nakamura H, Sekimoto T, Oike Y, Imaizumi T, Saito F, Muta M, Soejima Y, Utoh A, Nakagata N, Araki M, Yamamura K and Araki K

    Institute of Molecular Embryology and Genetics, Kumamoto University, Kuhonji 4-24-1, Kumamoto 862-0976, Japan.

    We have developed a new exchangeable gene trap vector, pU-17, carrying the intron-lox71-splicing acceptor (SA)-beta geo-loxP-pA-lox2272-pSP73-lox511. The SA contains three stop codons in-frame with the ATG of beta galactosidase/neomycin-resistance fusion gene (beta geo) that can function in promoter trapping. We found that the trap vector was highly selective for integrations in the introns adjacent to the exon containing the start codon. Furthermore, by using the Cre-mutant lox system, we successfully replaced the beta geo gene with the enhanced green fluorescent protein (EGFP) gene, established mouse lines with the replaced clones, removed the selection marker gene by mating with Flp-deleter mice, and confirmed that the replaced EGFP gene was expressed in the same pattern as the beta geo gene. Thus, using this pU-17 trap vector, we can initially carry out random mutagenesis, and then convert it to a gain-of-function mutation by replacing the beta geo gene with any gene of interest to be expressed under the control of the trapped promoter through Cre-mediated recombination.

    Development, growth & differentiation 2005;47;3;163-72

  • The serotonin 5-HT2A and 5-HT2C receptors interact with specific sets of PDZ proteins.

    Bécamel C, Gavarini S, Chanrion B, Alonso G, Galéotti N, Dumuis A, Bockaert J and Marin P

    UPR CNRS 2580 and CNRS UMR 5101, 141 rue de la Cardonille, 34094 Montpellier Cedex 5, France.

    The 5-hydroxytryptamine type 2A (5-HT(2A)) receptor and the 5-HT(2C) receptor are closely related members of the G-protein-coupled receptors activated by serotonin that share very similar pharmacological profiles and cellular signaling pathways. These receptors express a canonical class I PDZ ligand (SXV) at their C-terminal extremity. Here, we have identified proteins that interact with the PDZ ligand of the 5-HT(2A) and 5-HT(2C) receptors by a proteomic approach associating affinity chromatography using immobilized synthetic peptides encompassing the PDZ ligand and mass spectrometry. We report that both receptor C termini interact with specific sets of PDZ proteins in vitro. The 5-HT(2C) receptor but not the 5-HT(2A) receptor binds to the Veli-3.CASK.Mint1 ternary complex and to SAP102. In addition, the 5-HT(2C) receptor binds more strongly to PSD-95 and MPP-3 than the 5-HT(2A) receptor. In contrast, a robust interaction between the 5-HT(2A) receptor and the channel-interacting PDZ protein CIPP was found, whereas CIPP did not significantly associate with the 5-HT(2C) receptor. We also show that residues located at the -1 position and upstream the PDZ ligand in the C terminus of the 5-HT(2A) and 5-HT(2C) receptors are major determinants in their interaction with specific PDZ proteins. Immunofluorescence and electron microscopy studies strongly suggested that these specific interactions also take place in living cells and that the 5-HT(2) receptor-PDZ protein complexes occur in intracellular compartments. The interaction of the 5-HT(2A) and the 5-HT(2C) receptor with specific sets of PDZ proteins may contribute to their different signal transduction properties.

    The Journal of biological chemistry 2004;279;19;20257-66

  • A collection of cDNAs enriched in upper cortical layers of the embryonic mouse brain.

    García-Frigola C, Burgaya F, Calbet M, López-Domènech G, de Lecea L and Soriano E

    IRBB/PCB and Department of Cell Biology, Faculty of Biology, University of Barcelona, 08071 Barcelona, Spain.

    In an attempt to elucidate the molecular basis of neuronal migration and corticogenesis, we performed subtractive hybridization of mRNAs from the upper cortical layers (layer I and upper cortical plate) against mRNAs from the remaining cerebral cortex at E15-E16. We obtained a collection of subtracted cDNA clones and analyzed their 3' UTR sequences, 47% of which correspond to EST sequences, and may represent novel products. Among the cloned sequences, we identified gene products that have not been reported in brain or in the cerebral cortex before. We examined the expression pattern of 39 subtracted clones, which was enriched in the upper layers of the cerebral cortex at embryonic stages. The expression of most clones is developmentally regulated, and especially high in embryonic and early postnatal stages. Four of the unknown clones were studied in more detail and identified as a new member of the tetraspanin superfamily, a putative RNA binding protein, a specific product of the adult dentate gyrus and a protein containing a beta-catenin repeat. We thus cloned a collection of subtracted cDNAs coding for protein products that may be involved in the development of the cerebral cortex.

    Funded by: NIMH NIH HHS: R01MH58543

    Brain research. Molecular brain research 2004;122;2;133-50

  • Transcriptome analysis of mouse stem cells and early embryos.

    Sharov AA, Piao Y, Matoba R, Dudekula DB, Qian Y, VanBuren V, Falco G, Martin PR, Stagg CA, Bassey UC, Wang Y, Carter MG, Hamatani T, Aiba K, Akutsu H, Sharova L, Tanaka TS, Kimber WL, Yoshikawa T, Jaradat SA, Pantano S, Nagaraja R, Boheler KR, Taub D, Hodes RJ, Longo DL, Schlessinger D, Keller J, Klotz E, Kelsoe G, Umezawa A, Vescovi AL, Rossant J, Kunath T, Hogan BL, Curci A, D'Urso M, Kelso J, Hide W and Ko MS

    National Institute on Aging, Baltimore, Maryland, USA.

    Understanding and harnessing cellular potency are fundamental in biology and are also critical to the future therapeutic use of stem cells. Transcriptome analysis of these pluripotent cells is a first step towards such goals. Starting with sources that include oocytes, blastocysts, and embryonic and adult stem cells, we obtained 249,200 high-quality EST sequences and clustered them with public sequences to produce an index of approximately 30,000 total mouse genes that includes 977 previously unidentified genes. Analysis of gene expression levels by EST frequency identifies genes that characterize preimplantation embryos, embryonic stem cells, and adult stem cells, thus providing potential markers as well as clues to the functional features of these cells. Principal component analysis identified a set of 88 genes whose average expression levels decrease from oocytes to blastocysts, stem cells, postimplantation embryos, and finally to newborn tissues. This can be a first step towards a possible definition of a molecular scale of cellular potency. The sequences and cDNA clones recovered in this work provide a comprehensive resource for genes functioning in early mouse embryos and stem cells. The nonrestricted community access to the resource can accelerate a wide range of research, particularly in reproductive and regenerative medicine.

    Funded by: NCI NIH HHS: N01-CO-5600

    PLoS biology 2003;1;3;E74

  • 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

  • NMDA receptor trafficking through an interaction between PDZ proteins and the exocyst complex.

    Sans N, Prybylowski K, Petralia RS, Chang K, Wang YX, Racca C, Vicini S and Wenthold RJ

    Laboratory of Neurochemistry, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Building 50, Room 4146, 50 South Drive, Bethesda, MD 20892-8027, USA. sansn@nidcd.nih.gov

    NMDA (N-methyl-D-aspartate) receptors (NMDARs) are targeted to dendrites and anchored at the post-synaptic density (PSD) through interactions with PDZ proteins. However, little is known about how these receptors are sorted from the endoplasmic reticulum and Golgi apparatus to the synapse. Here, we find that synapse-associated protein 102 (SAP102) interacts with the PDZ-binding domain of Sec8, a member of the exocyst complex. Our results show that interactions between SAP102 and Sec8 are involved in the delivery of NMDARs to the cell surface in heterologous cells and neurons. Furthermore, they suggest that an exocyst-SAP102-NMDAR complex is an important component of NMDAR trafficking.

    Nature cell biology 2003;5;6;520-30

  • 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

  • Identification of multiple binding partners for the amino-terminal domain of synapse-associated protein 97.

    Karnak D, Lee S and Margolis B

    Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.

    Multiprotein complexes mediate static and dynamic functions to establish and maintain cell polarity in both epithelial cells and neurons. Membrane-associated guanylate kinase (MAGUK) proteins are thought to be scaffolding molecules in these processes and bind multiple proteins via their obligate postsynaptic density (PSD)-95/Disc Large/Zona Occludens-1, Src homology 3, and guanylate kinase-like domains. Subsets of MAGUK proteins have additional protein-protein interaction domains. An additional domain we identified in SAP97 called the MAGUK recruitment (MRE) domain binds the LIN-2,7 amino-terminal (L27N) domain of mLIN-2/CASK, a MAGUK known to bind mLIN-7. Here we show that SAP97 binds two other mLIN-7 binding MAGUK proteins. One of these MAGUK proteins, DLG3, coimmunoprecipitates with SAP97 in lysates from rat brain and transfected Madin-Darby canine kidney cells. This interaction requires the MRE domain of SAP97 and surprisingly, both the L27N and L27 carboxyl-terminal (L27C) domains of DLG3. We also demonstrate that SAP97 can interact with the MAGUK protein, DLG2, but not the highly related protein, PALS2. The ability of SAP97 to interact with multiple MAGUK proteins is likely to be important for the targeting of specific protein complexes in polarized cells.

    Funded by: NIDDK NIH HHS: 2-P50-DK39255; NIGMS NIH HHS: 5-T32-GM07544, GM08353

    The Journal of biological chemistry 2002;277;48;46730-5

  • 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

  • Exchangeable gene trap using the Cre/mutated lox system.

    Araki K, Imaizumi T, Sekimoto T, Yoshinobu K, Yoshimuta J, Akizuki M, Miura K, Araki M and Yamamura K

    Institute of Molecular Embryology and Genetics, Kumamoto University School of Medicine, Japan. yamamura@gpo.kumamoto-u.ac.jp

    The gene trap technique is a powerful approach for characterizing and mutating genes involved in mouse development. However, one shortcoming of gene trapping is the relative inability to induce subtle mutations. This problem can be overcome by introducing a knock-in system into the gene trap strategy. Here, we have constructed a new gene trap vector, pU-Hachi, employing the Cre-mutated lox system (Araki et al., 1997), in which a pair of mutant lox, lox71 and lox66, was used to promote targeted integrative reaction by Cre recombinase. The pU-Hachi carries splicing acceptor (SA)-lox71-internal ribosomal entry site (IRES)-beta-geo-pA-loxP-pA-pUC. By using this vector, we can carry out random insertional mutagenesis as the first step, and then we can replace the beta-geo gene with any gene of interest through Cre-mediated integration. We have isolated 109 trap clones electroporated with pU-Hachi, and analyzed their integration patterns by Southern blotting to select those carrying a single copy of the trap vector. By use of some of these clones, we have succeeded in exchanging the reporter gene at high efficiency, ranging between 20-80%. This integration system is also quite useful for plasmid rescue to recover flanking genomic sequences, because a plasmid vector sequence can be introduced even when the pUC sequence of the trap vector is lost through integration into the genome. Thus, this method, termed exchangeable gene trapping, has many advantages as the trapped clones can be utilized to express genes with any type of mutation.

    Cellular and molecular biology (Noisy-le-Grand, France) 1999;45;5;737-50

  • cDNA sequence and chromosomal localization of mouse Dlgh3 gene adjacent to the BRCA1 tumor suppressor locus.

    Lin L, Peters LL, Ciciotte SL and Chishti AH

    Laboratory of Tumor Cell Biology, St. Elizabeth's Medical Center, Tufts University School of Medicine, ACH4, 736 Cambridge Street, Boston, MA 02135, USA.

    Membrane associated guanylate kinase homologues (MAGUKs) function in tumor suppression and receptor clustering pathways presumably by modulating signaling events at the interface of the membrane cytoskeleton. The p55 subclass of MAGUKs includes two novel cDNAs that were originally identified by virtue of their genomic location to human chromosome 17q12-21 where the BRCA1 tumor suppressor gene has been mapped. The predicted primary structure of the human MPP3 contains a single copy of the PDZ domain, an SH3 motif, and a carboxy-terminal guanylate kinase-like domain. Here we report the full-length coding cDNA sequence of the mouse homologue of MPP3. The translated amino acid sequence of murine Dlgh3 contains 568 amino acids that show 87% sequence identity with the human MPP3 protein. Northern blot analysis shows abundant expression of a approximately 3.0 kb transcript of Dlgh3 in mouse brain and skeletal muscle, and a relatively less abundant approximately 5.0 kb transcript in skeletal muscle, testis, kidney, and lung. Using an interspecific backcross panel, the Dlgh3 gene was mapped to a segment of mouse chromosome 11 that is conserved with human chromosome 17q12-21. The close proximity of murine Dlgh3 gene to the BRCA1 locus and the high conservation of the primary structure of human and murine proteins provide a framework for testing the role of Dlgh3 in cell proliferation pathways using the mouse as a model system.

    Funded by: NCI NIH HHS: CA66263; NHLBI NIH HHS: HL55321, R01 HL055321

    Biochimica et biophysica acta 1998;1443;1-2;211-6

Gene lists (9)

Gene List Source Species Name Description Gene count
L00000001 G2C Mus musculus Mouse PSD Mouse PSD adapted from Collins et al (2006) 1080
L00000007 G2C Mus musculus Mouse NRC Mouse NRC adapted from Collins et al (2006) 186
L00000008 G2C Mus musculus Mouse PSP Mouse PSP adapted from Collins et al (2006) 1121
L00000019 G2C Mus musculus Pocklington M1 Cluster 1 (mouse) from Pocklington et al (2006) 21
L00000050 G2C Mus musculus TAP-PSD-95-CORE TAP-PSD-95 pull-down core list 120
L00000060 G2C Mus musculus BAYES-COLLINS-HUMAN-PSD-CONSENSUS Human cortex PSD consensus (ortho) 748
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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