Common DISC1 Polymorphisms Disrupt Wnt/GSK3β Signaling and Brain Development
Disrupted in Schizophrenia-1 (DISC1) is a candidate gene for psychiatric disorders and has many roles during brain development. Common DISC1 polymorphisms (variants) are associated with neuropsychiatric phenotypes including altered cognition, brain structure, and function; however, it is unknown how...
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| Veröffentlicht in: | Neuron (Cambridge, Mass.) Mass.), 2011-11, Vol.72 (4), p.545-558 |
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| creator | Singh, Karun K. De Rienzo, Gianluca Drane, Laurel Mao, Yingwei Flood, Zachary Madison, Jon Ferreira, Manuel Bergen, Sarah King, Cillian Sklar, Pamela Sive, Hazel Tsai, Li-Huei |
| description | Disrupted in Schizophrenia-1 (DISC1) is a candidate gene for psychiatric disorders and has many roles during brain development. Common DISC1 polymorphisms (variants) are associated with neuropsychiatric phenotypes including altered cognition, brain structure, and function; however, it is unknown how this occurs. Here, we demonstrate using mouse, zebrafish, and human model systems that DISC1 variants are loss of function in Wnt/GSK3β signaling and disrupt brain development. The DISC1 variants A83V, R264Q, and L607F, but not S704C, do not activate Wnt signaling compared with wild-type DISC1 resulting in decreased neural progenitor proliferation. In zebrafish, R264Q and L607F could not rescue DISC1 knockdown-mediated aberrant brain development. Furthermore, human lymphoblast cell lines endogenously expressing R264Q displayed impaired Wnt signaling. Interestingly, S704C inhibited the migration of neurons in the developing neocortex. Our data demonstrate DISC1 variants impair Wnt signaling and brain development and elucidate a possible mechanism for their role in neuropsychiatric phenotypes.
► Zebrafish, mouse, and human model systems used to assay DISC1 genetic variants ► DISC1 variants inhibit Wnt signaling and neurogenesis via altered GSK3β interaction ► Human lymphoblast cells expressing human DISC1 variants have reduced Wnt signaling ► DISC1 S704C variant reduces neuronal migration |
| doi_str_mv | 10.1016/j.neuron.2011.09.030 |
| format | Article |
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► Zebrafish, mouse, and human model systems used to assay DISC1 genetic variants ► DISC1 variants inhibit Wnt signaling and neurogenesis via altered GSK3β interaction ► Human lymphoblast cells expressing human DISC1 variants have reduced Wnt signaling ► DISC1 S704C variant reduces neuronal migration</description><identifier>ISSN: 0896-6273</identifier><identifier>EISSN: 1097-4199</identifier><identifier>DOI: 10.1016/j.neuron.2011.09.030</identifier><identifier>PMID: 22099458</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Brain - growth & development ; Brain Chemistry - genetics ; Cell Line, Tumor ; Female ; Genetic Variation - genetics ; Glycogen Synthase Kinase 3 - genetics ; Glycogen Synthase Kinase 3 beta ; HEK293 Cells ; Humans ; Mice ; Nerve Tissue Proteins - genetics ; Phenotype ; Polymorphism, Genetic - genetics ; Pregnancy ; Signal Transduction - genetics ; Wnt3A Protein - genetics ; Zebrafish</subject><ispartof>Neuron (Cambridge, Mass.), 2011-11, Vol.72 (4), p.545-558</ispartof><rights>2011 Elsevier Inc.</rights><rights>Copyright © 2011 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c462t-3c9cc575563f0ce1f180feaf899fd9ba5b37d19b45042ca64d3d7fcdb5068cfc3</citedby><cites>FETCH-LOGICAL-c462t-3c9cc575563f0ce1f180feaf899fd9ba5b37d19b45042ca64d3d7fcdb5068cfc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.neuron.2011.09.030$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,315,782,786,887,3552,27931,27932,46002</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22099458$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Singh, Karun K.</creatorcontrib><creatorcontrib>De Rienzo, Gianluca</creatorcontrib><creatorcontrib>Drane, Laurel</creatorcontrib><creatorcontrib>Mao, Yingwei</creatorcontrib><creatorcontrib>Flood, Zachary</creatorcontrib><creatorcontrib>Madison, Jon</creatorcontrib><creatorcontrib>Ferreira, Manuel</creatorcontrib><creatorcontrib>Bergen, Sarah</creatorcontrib><creatorcontrib>King, Cillian</creatorcontrib><creatorcontrib>Sklar, Pamela</creatorcontrib><creatorcontrib>Sive, Hazel</creatorcontrib><creatorcontrib>Tsai, Li-Huei</creatorcontrib><title>Common DISC1 Polymorphisms Disrupt Wnt/GSK3β Signaling and Brain Development</title><title>Neuron (Cambridge, Mass.)</title><addtitle>Neuron</addtitle><description>Disrupted in Schizophrenia-1 (DISC1) is a candidate gene for psychiatric disorders and has many roles during brain development. Common DISC1 polymorphisms (variants) are associated with neuropsychiatric phenotypes including altered cognition, brain structure, and function; however, it is unknown how this occurs. Here, we demonstrate using mouse, zebrafish, and human model systems that DISC1 variants are loss of function in Wnt/GSK3β signaling and disrupt brain development. The DISC1 variants A83V, R264Q, and L607F, but not S704C, do not activate Wnt signaling compared with wild-type DISC1 resulting in decreased neural progenitor proliferation. In zebrafish, R264Q and L607F could not rescue DISC1 knockdown-mediated aberrant brain development. Furthermore, human lymphoblast cell lines endogenously expressing R264Q displayed impaired Wnt signaling. Interestingly, S704C inhibited the migration of neurons in the developing neocortex. Our data demonstrate DISC1 variants impair Wnt signaling and brain development and elucidate a possible mechanism for their role in neuropsychiatric phenotypes.
► Zebrafish, mouse, and human model systems used to assay DISC1 genetic variants ► DISC1 variants inhibit Wnt signaling and neurogenesis via altered GSK3β interaction ► Human lymphoblast cells expressing human DISC1 variants have reduced Wnt signaling ► DISC1 S704C variant reduces neuronal migration</description><subject>Animals</subject><subject>Brain - growth & development</subject><subject>Brain Chemistry - genetics</subject><subject>Cell Line, Tumor</subject><subject>Female</subject><subject>Genetic Variation - genetics</subject><subject>Glycogen Synthase Kinase 3 - genetics</subject><subject>Glycogen Synthase Kinase 3 beta</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Mice</subject><subject>Nerve Tissue Proteins - genetics</subject><subject>Phenotype</subject><subject>Polymorphism, Genetic - genetics</subject><subject>Pregnancy</subject><subject>Signal Transduction - genetics</subject><subject>Wnt3A Protein - genetics</subject><subject>Zebrafish</subject><issn>0896-6273</issn><issn>1097-4199</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9Uctu1DAUtRCIDoU_QCg7Vkmv40fiDRJMaaloBdKAWFqOH1OPEjvYyUj9rX4I30SqKQU2Xd3FPY97z0HoNYYKA-YnuyrYOcVQ1YBxBaICAk_QCoNoSoqFeIpW0Ape8rohR-hFzjsATJnAz9FRXYMQlLUrdLWOwxBDcXqxWePia-xvhpjGa5-HXJz6nOZxKn6E6eR885n8ui02fhtU78O2UMEUH5LyC9XubR_HwYbpJXrmVJ_tq_t5jL6fffy2_lRefjm_WL-_LDXl9VQSLbRmDWOcONAWO9yCs8q1QjgjOsU60hgsOsqA1lpxaohpnDYdA95qp8kxenfQHedusEYv1kn1ckx-UOlGRuXl_5vgr-U27iUhbcNbugi8vRdI8eds8yQHn7XtexVsnLMUwHjDGa0XJD0gdYo5J-seXDDIuyLkTh6KkHdFSBByKWKhvfn3wgfSn-T_vmCXnPbeJpm1t0Fb45PVkzTRP-7wG7fyniI</recordid><startdate>20111117</startdate><enddate>20111117</enddate><creator>Singh, Karun K.</creator><creator>De Rienzo, Gianluca</creator><creator>Drane, Laurel</creator><creator>Mao, Yingwei</creator><creator>Flood, Zachary</creator><creator>Madison, Jon</creator><creator>Ferreira, Manuel</creator><creator>Bergen, Sarah</creator><creator>King, Cillian</creator><creator>Sklar, Pamela</creator><creator>Sive, Hazel</creator><creator>Tsai, Li-Huei</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20111117</creationdate><title>Common DISC1 Polymorphisms Disrupt Wnt/GSK3β Signaling and Brain Development</title><author>Singh, Karun K. ; De Rienzo, Gianluca ; Drane, Laurel ; Mao, Yingwei ; Flood, Zachary ; Madison, Jon ; Ferreira, Manuel ; Bergen, Sarah ; King, Cillian ; Sklar, Pamela ; Sive, Hazel ; Tsai, Li-Huei</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c462t-3c9cc575563f0ce1f180feaf899fd9ba5b37d19b45042ca64d3d7fcdb5068cfc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Animals</topic><topic>Brain - growth & development</topic><topic>Brain Chemistry - genetics</topic><topic>Cell Line, Tumor</topic><topic>Female</topic><topic>Genetic Variation - genetics</topic><topic>Glycogen Synthase Kinase 3 - genetics</topic><topic>Glycogen Synthase Kinase 3 beta</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Mice</topic><topic>Nerve Tissue Proteins - genetics</topic><topic>Phenotype</topic><topic>Polymorphism, Genetic - genetics</topic><topic>Pregnancy</topic><topic>Signal Transduction - genetics</topic><topic>Wnt3A Protein - genetics</topic><topic>Zebrafish</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Singh, Karun K.</creatorcontrib><creatorcontrib>De Rienzo, Gianluca</creatorcontrib><creatorcontrib>Drane, Laurel</creatorcontrib><creatorcontrib>Mao, Yingwei</creatorcontrib><creatorcontrib>Flood, Zachary</creatorcontrib><creatorcontrib>Madison, Jon</creatorcontrib><creatorcontrib>Ferreira, Manuel</creatorcontrib><creatorcontrib>Bergen, Sarah</creatorcontrib><creatorcontrib>King, Cillian</creatorcontrib><creatorcontrib>Sklar, Pamela</creatorcontrib><creatorcontrib>Sive, Hazel</creatorcontrib><creatorcontrib>Tsai, Li-Huei</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Neuron (Cambridge, Mass.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Singh, Karun K.</au><au>De Rienzo, Gianluca</au><au>Drane, Laurel</au><au>Mao, Yingwei</au><au>Flood, Zachary</au><au>Madison, Jon</au><au>Ferreira, Manuel</au><au>Bergen, Sarah</au><au>King, Cillian</au><au>Sklar, Pamela</au><au>Sive, Hazel</au><au>Tsai, Li-Huei</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Common DISC1 Polymorphisms Disrupt Wnt/GSK3β Signaling and Brain Development</atitle><jtitle>Neuron (Cambridge, Mass.)</jtitle><addtitle>Neuron</addtitle><date>2011-11-17</date><risdate>2011</risdate><volume>72</volume><issue>4</issue><spage>545</spage><epage>558</epage><pages>545-558</pages><issn>0896-6273</issn><eissn>1097-4199</eissn><abstract>Disrupted in Schizophrenia-1 (DISC1) is a candidate gene for psychiatric disorders and has many roles during brain development. Common DISC1 polymorphisms (variants) are associated with neuropsychiatric phenotypes including altered cognition, brain structure, and function; however, it is unknown how this occurs. Here, we demonstrate using mouse, zebrafish, and human model systems that DISC1 variants are loss of function in Wnt/GSK3β signaling and disrupt brain development. The DISC1 variants A83V, R264Q, and L607F, but not S704C, do not activate Wnt signaling compared with wild-type DISC1 resulting in decreased neural progenitor proliferation. In zebrafish, R264Q and L607F could not rescue DISC1 knockdown-mediated aberrant brain development. Furthermore, human lymphoblast cell lines endogenously expressing R264Q displayed impaired Wnt signaling. Interestingly, S704C inhibited the migration of neurons in the developing neocortex. Our data demonstrate DISC1 variants impair Wnt signaling and brain development and elucidate a possible mechanism for their role in neuropsychiatric phenotypes.
► Zebrafish, mouse, and human model systems used to assay DISC1 genetic variants ► DISC1 variants inhibit Wnt signaling and neurogenesis via altered GSK3β interaction ► Human lymphoblast cells expressing human DISC1 variants have reduced Wnt signaling ► DISC1 S704C variant reduces neuronal migration</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>22099458</pmid><doi>10.1016/j.neuron.2011.09.030</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| source | Elsevier ScienceDirect Journals Complete - AutoHoldings; MEDLINE; Cell Press Free Archives; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Animals Brain - growth & development Brain Chemistry - genetics Cell Line, Tumor Female Genetic Variation - genetics Glycogen Synthase Kinase 3 - genetics Glycogen Synthase Kinase 3 beta HEK293 Cells Humans Mice Nerve Tissue Proteins - genetics Phenotype Polymorphism, Genetic - genetics Pregnancy Signal Transduction - genetics Wnt3A Protein - genetics Zebrafish |
| title | Common DISC1 Polymorphisms Disrupt Wnt/GSK3β Signaling and Brain Development |
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