G2Cdb::Gene report

Gene id
G00000862
Gene symbol
Shank1 (MGI)
Species
Mus musculus
Description
SH3/ankyrin domain gene 1
Orthologue
G00002111 (Homo sapiens)

Databases (6)

Curated Gene
OTTMUSG00000016443 (Vega mouse gene)
Gene
ENSMUSG00000038738 (Ensembl mouse gene)
243961 (Entrez Gene)
28 (G2Cdb plasticity & disease)
Literature
604999 (OMIM)
Marker Symbol
MGI:3613677 (MGI)

Alleles (1)

Literature (10)

Pubmed - other

  • Sociability and motor functions in Shank1 mutant mice.

    Silverman JL, Turner SM, Barkan CL, Tolu SS, Saxena R, Hung AY, Sheng M and Crawley JN

    Laboratory of Behavioral Neuroscience, Intramural Research Program, National Institute of Mental Health, NIH, Bethesda, MD 20892, USA. silvermanj@mail.nih.gov

    Autism is a neurodevelopmental disorder characterized by aberrant reciprocal social interactions, impaired communication, and repetitive behaviors. While the etiology remains unclear, strong evidence exists for a genetic component, and several synaptic genes have been implicated. SHANK genes encode a family of synaptic scaffolding proteins located postsynaptically on excitatory synapses. Mutations in SHANK genes have been detected in several autistic individuals. To understand the consequences of SHANK mutations relevant to the diagnostic and associated symptoms of autism, comprehensive behavioral phenotyping on a line of Shank1 mutant mice was conducted on multiple measures of social interactions, social olfaction, repetitive behaviors, anxiety-related behaviors, motor functions, and a series of control measures for physical abilities. Results from our comprehensive behavioral phenotyping battery indicated that adult Shank1 null mutant mice were similar to their wildtype and heterozygous littermates on standardized measures of general health, neurological reflexes and sensory skills. Motor functions were reduced in the null mutants on open field activity, rotarod, and wire hang, replicating and extending previous findings (Hung et al., 2008). A partial anxiety-like phenotype was detected in the null mutants in some components of the light ↔ dark task, as previously reported (Hung et al., 2008) but not in the elevated plus-maze. Juvenile reciprocal social interactions did not differ across genotypes. Interpretation of adult social approach was confounded by a lack of normal sociability in wildtype and heterozygous littermates. All genotypes were able to discriminate social odors on an olfactory habituation/dishabituation task. All genotypes displayed relatively high levels of repetitive self-grooming. Our findings support the interpretation that Shank1 null mice do not demonstrate autism-relevant social interaction deficits, but confirm and extend a role for Shank1 in motor functions.

    Funded by: Intramural NIH HHS: Z99 MH999999

    Brain research 2011;1380;120-37

  • Fragile X mental retardation protein regulates the levels of scaffold proteins and glutamate receptors in postsynaptic densities.

    Schütt J, Falley K, Richter D, Kreienkamp HJ and Kindler S

    Institute for Human Genetics, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.

    Functional absence of fragile X mental retardation protein (FMRP) causes the fragile X syndrome, a hereditary form of mental retardation characterized by a change in dendritic spine morphology. The RNA-binding protein FMRP has been implicated in regulating postsynaptic protein synthesis. Here we have analyzed whether the abundance of scaffold proteins and neurotransmitter receptor subunits in postsynaptic densities (PSDs) is altered in the neocortex and hippocampus of FMRP-deficient mice. Whereas the levels of several PSD components are unchanged, concentrations of Shank1 and SAPAP scaffold proteins and various glutamate receptor subunits are altered in both adult and juvenile knock-out mice. With the exception of slightly increased hippocampal SAPAP2 mRNA levels in adult animals, altered postsynaptic protein concentrations do not correlate with similar changes in total and synaptic levels of corresponding mRNAs. Thus, loss of FMRP in neurons appears to mainly affect the translation and not the abundance of particular brain transcripts. Semi-quantitative analysis of RNA levels in FMRP immunoprecipitates showed that in the mouse brain mRNAs encoding PSD components, such as Shank1, SAPAP1-3, PSD-95, and the glutamate receptor subunits NR1 and NR2B, are associated with FMRP. Luciferase reporter assays performed in primary cortical neurons from knock-out and wild-type mice indicate that FMRP silences translation of Shank1 mRNAs via their 3'-untranslated region. Activation of metabotropic glutamate receptors relieves translational suppression. As Shank1 controls dendritic spine morphology, our data suggest that dysregulation of Shank1 synthesis may significantly contribute to the abnormal spine development and function observed in brains of fragile X syndrome patients.

    The Journal of biological chemistry 2009;284;38;25479-87

  • Shank1 mRNA: dendritic transport by kinesin and translational control by the 5'untranslated region.

    Falley K, Schütt J, Iglauer P, Menke K, Maas C, Kneussel M, Kindler S, Wouters FS, Richter D and Kreienkamp HJ

    Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf; Martinistrasse 52; 20246 Hamburg, Germany.

    Dendritic mRNA transport coupled with local regulation of translation enables neurons to selectively alter the protein composition of individual postsynaptic sites. We have analyzed dendritic localization of shank1 mRNAs; shank proteins (shank1-3) are scaffolding molecules of the postsynaptic density (PSD) of excitatory synapses, which are crucial for PSD assembly and the formation of dendritic spines. Live cell imaging demonstrates saltatory movements of shank1 mRNA containing granules along microtubules in both anterograde and retrograde directions. A population of brain messenger ribonucleoprotein particles (mRNPs) containing shank1 mRNAs associates with the cargo-binding domain of the motor protein KIF5C. Through expression of dominant negative proteins, we show that dendritic targeting of shank1 mRNA granules involves KIF5C and the KIF5-associated RNA-binding protein staufen1. While transport of shank1 mRNAs follows principles previously outlined for other dendritic transcripts, shank1 mRNAs are distinguished by their translational regulation. Translation is strongly inhibited by a GC-rich 5(')untranslated region; in addition, internal ribosomal entry sites previously detected in other dendritic transcripts are absent in the shank1 mRNA. A concept emerges from our data in which dendritic transport of different mRNAs occurs collectively via a staufen1- and KIF5-dependent pathway, whereas their local translation is controlled individually by unique cis-acting elements.

    Traffic (Copenhagen, Denmark) 2009;10;7;844-57

  • The insulin receptor substrate of 53 kDa (IRSp53) limits hippocampal synaptic plasticity.

    Sawallisch C, Berhörster K, Disanza A, Mantoani S, Kintscher M, Stoenica L, Dityatev A, Sieber S, Kindler S, Morellini F, Schweizer M, Boeckers TM, Korte M, Scita G and Kreienkamp HJ

    Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, 20246 Hamburg, Germany.

    IRSp53 is an essential intermediate between the activation of Rac and Cdc42 GTPases and the formation of cellular protrusions; it affects cell shape by coupling membrane-deforming activity with the actin cytoskeleton. IRSp53 is highly expressed in neurons where it is also an abundant component of the postsynaptic density (PSD). Here we analyze the physiological function of this protein in the mouse brain by generating IRSp53-deficient mice. Neurons in the hippocampus of young and adult knock-out (KO) mice do not exhibit morphological abnormalities in vivo. Conversely, primary cultured neurons derived from IRSp53 KO mice display retarded dendritic development in vitro. On a molecular level, Eps8 cooperates with IRSp53 to enhance actin bundling and interacts with IRSp53 in developing neurons. However, postsynaptic Shank proteins which are expressed at high levels in mature neurons compete with Eps8 to block actin bundling. In electrophysiological experiments the removal of IRSp53 increases synaptic plasticity as measured by augmented long term potentiation and paired-pulse facilitation. A primarily postsynaptic role of IRSp53 is underscored by the decreased size of the PSDs, which display increased levels of N-methyl-d-aspartate receptor subunits in IRSp53 KO animals. Our data suggest that the incorporation of IRSp53 into the PSD enables the protein to limit the number of postsynaptic glutamate receptors and thereby affect synaptic plasticity rather than dendritic morphology. Consistent with altered synaptic plasticity, IRSp53-deficient mice exhibit cognitive deficits in the contextual fear-conditioning paradigm.

    The Journal of biological chemistry 2009;284;14;9225-36

  • Smaller dendritic spines, weaker synaptic transmission, but enhanced spatial learning in mice lacking Shank1.

    Hung AY, Futai K, Sala C, Valtschanoff JG, Ryu J, Woodworth MA, Kidd FL, Sung CC, Miyakawa T, Bear MF, Weinberg RJ and Sheng M

    The Institute of Physical and Chemical Research (RIKEN)-Massachusetts Institute of Technology Neuroscience Research Center, Cambridge, Massachusetts 02139, USA.

    Experience-dependent changes in the structure of dendritic spines may contribute to learning and memory. Encoded by three genes, the Shank family of postsynaptic scaffold proteins are abundant and enriched in the postsynaptic density (PSD) of central excitatory synapses. When expressed in cultured hippocampal neurons, Shank promotes the maturation and enlargement of dendritic spines. Recently, Shank3 has been genetically implicated in human autism, suggesting an important role for Shank proteins in normal cognitive development. Here, we report the phenotype of Shank1 knock-out mice. Shank1 mutants showed altered PSD protein composition; reduced size of dendritic spines; smaller, thinner PSDs; and weaker basal synaptic transmission. Standard measures of synaptic plasticity were normal. Behaviorally, they had increased anxiety-related behavior and impaired contextual fear memory. Remarkably, Shank1-deficient mice displayed enhanced performance in a spatial learning task; however, their long-term memory retention in this task was impaired. These results affirm the importance of Shank1 for synapse structure and function in vivo, and they highlight a differential role for Shank1 in specific cognitive processes, a feature that may be relevant to human autism spectrum disorders.

    Funded by: NINDS NIH HHS: K08 NS041411, K08 NS41411, R01 NS039444, R01 NS039444-07

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2008;28;7;1697-708

  • Nicotine regulates multiple synaptic proteins by inhibiting proteasomal activity.

    Rezvani K, Teng Y, Shim D and De Biasi M

    Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA.

    Ubiquitination regulates the degradation, membrane trafficking, and transcription of proteins. At mammalian synapses, the ubiquitin-proteasome system (UPS) influences synaptic transmission and plasticity. Nicotine also has the ability to affect synaptic function via mechanisms that remain partially unknown. We found that nicotine, at concentrations achieved by smokers, reduced proteasomal activity, produced accumulation of ubiquitinated synaptic proteins, and increased total protein levels. In particular, a 24 h exposure to nicotine decreased proteasome-dependent degradation of the alpha7 nicotinic acetylcholine receptor (nAChR) subunit, as indicated by the accumulation of ubiquitinated alpha7. The same nicotine treatment increased the levels of the AMPA glutamate receptor subunit GluR1, the NMDA receptor subunit NR2A, the metabotropic receptor mGluR1alpha, the plasticity factor Homer-1A, and the scaffolding postsynaptic density protein PSD-95, whereas the levels of another scaffolding protein, Shank, were reduced. These changes were associated with an inhibition of proteasomal chymotrypsin-like activity by nicotine. The nAChR antagonist mecamylamine was only partially able to block the effects of nicotine on the UPS, indicating that nAChR activation does not completely explain nicotine-induced inhibition of proteasomal catalytic activity. A competition binding assay suggested a direct interaction between nicotine and the 20S proteasome. These results suggest that the UPS might participate in nicotine-dependent synaptic plasticity.

    Funded by: NIDA NIH HHS: DA017173

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2007;27;39;10508-19

  • Direct interaction of post-synaptic density-95/Dlg/ZO-1 domain-containing synaptic molecule Shank3 with GluR1 alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor.

    Uchino S, Wada H, Honda S, Nakamura Y, Ondo Y, Uchiyama T, Tsutsumi M, Suzuki E, Hirasawa T and Kohsaka S

    Department of Neurochemistry, National Institute of Neuroscience, Kodaira, Tokyo, Japan.

    A class of scaffolding protein containing the post-synaptic density-95/Dlg/ZO-1 (PDZ) domain is thought to be involved in synaptic trafficking of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors during development. To clarify the molecular mechanism of AMPA receptor trafficking, we performed a yeast two-hybrid screening system using the cytoplasmic tail of the GluR1 subunit of AMPA receptor as a bait and identified a synaptic molecule, Shank3/ProSAP2, as a GluR1 subunit-interacting molecule. Shank3 is a PDZ domain-containing multidomain protein and is predominantly expressed in developing neurons. Using the glutathione S-transferase pull-down assay and immunoprecipitation technique we demonstrated that the GluR1 subunit directly binds to the PDZ domain of Shank3 via its carboxyl terminal PDZ-binding motif. We raised anti-Shank3 antibody to investigate the expression of Shank3 in cortical neurons. The pattern of Shank3 immunoreactivity was strikingly punctate, mainly observed in the spines, and closely matched the pattern of post-synaptic density-95 immunoreactivity, indicating that Shank3 is colocalized with post-synaptic density-95 in the same spines. When Shank3 and the GluR1 subunit were overexpressed in primary cortical neurons, they were also colocalized in the spines. Taken together with the biochemical interaction of Shank3 with the GluR1 subunit, these results suggest that Shank3 is an important molecule that interacts with GluR1 AMPA receptor at synaptic sites of developing neurons.

    Journal of neurochemistry 2006;97;4;1203-14

  • Immunohistochemical distribution of MIZIP and its co-expression with the Melanin-concentrating hormone receptor 1 in the adult rodent brain.

    Francke F, Richter D and Bächner D

    Institute for Cell Biochemistry and Clinical Neurobiology, University Hospital Hamburg-Eppendorf, D-20246 Hamburg, Germany.

    We have recently identified a Melanin-concentrating hormone receptor 1 interacting zinc-finger protein (MIZIP) from a human brain cDNA library. Here, we report the generation of a specific antibody against MIZIP and its distribution in rodent tissues using immunoblotting and immunohistochemical techniques. MIZIP was detected as a 27 kDa protein in brain, liver, and skeletal muscle, and to a lower extend, in lung, testis, and heart. Subcellular fractionation of adult mouse brain revealed the presence of MIZIP and MCHR1 in the cytoplasmic, membrane, and synaptosomal fraction, but not in a postsynaptic density preparation. In cultured rat, embryonic hippocampal neurons MIZIP is somatodendritically localized. In the adult rodent brain, MIZIP is widely distributed. High levels of expression were detected in brain regions involved in olfaction, feeding behavior, sensorimotor integration, and learning and memory, for example, the olfactory bulb, the olfactory tubercle, the caudate putamen, the thalamus and hypothalamus, the nucleus accumbens, the cerebral cortex, the hippocampus formation, and the cerebellum. Co-expression of MIZIP and MCHR1 was observed, for example, in pyramidal neurons of the cerebral cortex and hippocampus, in neurons of the olivary nucleus, lateral hypothalamus, nucleus accumbens, caudate putamen, pontine, and mesencephalic trigeminal nucleus. However, there are also differences in the expression patterns, for example, high expression of MCHR1 was detected in the lateral habenula, but no expression of MIZIP. These data support the notion that MIZIP might interact with MCHR1 in a cell type specific manner in vivo, suggesting a role in the regulation of MCH signalling in distinct regions of the mammalian brain.

    Brain research. Molecular brain research 2005;139;1;31-41

  • Direct interaction of GluRdelta2 with Shank scaffold proteins in cerebellar Purkinje cells.

    Uemura T, Mori H and Mishina M

    Department of Molecular Neurobiology and Pharmacology, Graduate School of Medicine, University of Tokyo, and Japan; SORST, Japan Science and Technology Corporation, Tokyo 113-0033, Japan.

    Glutamate receptor (GluR) delta2 selectively expressed in cerebellar Purkinje cells plays a central role in cerebellar long-term depression (LTD), motor learning, and formation of parallel fiber synapses. By yeast two-hybrid screening, we identified members of the Shank family of scaffold proteins as major GluRdelta2-interacting molecules. GluRdelta2 bound directly to the PDZ domain of Shank proteins through an internal motif in the carboxyl-terminal putative cytoplasmic domain. Shank1 and Shank2 proteins as well as GluRdelta2 proteins were localized in the dendritic spines of cultured Purkinje cells. Anti-GluRdelta2 antibodies immunoprecipitated Shank1, Shank2, Homer, and metabotropic GluR1alpha proteins from the synaptosomal membrane fractions of cerebella. Furthermore, Shank2 interacted with GRIP1 in the cerebellum. These results suggest that through Shank1 and Shank2, GluRdelta2 interacts with the metabotropic GluR1alpha, the AMPA-type GluR, and the inositol 1,4,5-trisphosphate receptor (IP3R) that are essential for cerebellar LTD.

    Molecular and cellular neurosciences 2004;26;2;330-41

  • Identification and developmental analysis of genes expressed by dopaminergic neurons of the substantia nigra pars compacta.

    Thuret S, Bhatt L, O'Leary DD and Simon HH

    Department of Anatomy and Cell Biology III, University of Heidelberg, 69120 Heidelberg, Germany.

    The hallmark of Parkinson's Disease is the degenerative loss of mesencephalic dopaminergic (mDA) neurons. Previous studies have shown that the homeobox transcription factors, engrailed-1 and -2, are essential for the survival of these cells. To identify genes downstream of engrailed-1 and -2, we performed a PCR-based differential display, comparing RNA from engrailed-1/2 double mutant and wild type ventral midbrain of different embryonic ages to adult olfactory bulb, a source of unrelated DA neurons. Here, we report the result of this experiment and describe the developmental expression pattern in the ventral midbrain of three of the isolated genes, HNF3alpha, synaptotagmin I, and Ebf3. Though not regulated by engrailed-1 and -2, the expression of all three genes is limited to mDA neurons and a few other brain areas. HNF3alpha appears in the precursors of mDA neurons at E9 and is expressed in the adult brain almost exclusively by this neuronal population. Synaptotagmin I is expressed from E14 into adulthood. Ebf3, in contrast, is transiently expressed during early postmitotic differentiation.

    Molecular and cellular neurosciences 2004;25;3;394-405

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
L00000005 G2C Mus musculus Mouse mGluR5 Mouse mGluR5 complex adapted from Collins et al (2006) 52
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
L00000025 G2C Mus musculus Pocklington M7 Cluster 7 (mouse) from Pocklington et al (2006) 4
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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