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dc.contributor.authorSingh, Karun K.
dc.contributor.authorDe Rienzo, Gianluca
dc.contributor.authorDrane, Laurel
dc.contributor.authorMao, Yingwei
dc.contributor.authorFlood, Zachary
dc.contributor.authorMadison, Jon M.
dc.contributor.authorFerreira, Manuel
dc.contributor.authorBergen, Sarah
dc.contributor.authorKing, Cillian
dc.contributor.authorSklar, Pamela
dc.contributor.authorSive, Hazel
dc.contributor.authorTsai, Li-Huei
dc.contributor.authorSingh, Karun K.
dc.date.accessioned2014-12-08T18:57:02Z
dc.date.available2014-12-08T18:57:02Z
dc.date.issued2011-11
dc.date.submitted2011-09
dc.identifier.issn08966273
dc.identifier.issn1097-4199
dc.identifier.urihttp://hdl.handle.net/1721.1/92214
dc.description.abstractDisrupted 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.en_US
dc.description.sponsorshipHuman Frontier Science Program (Strasbourg, France) (Fellowship)en_US
dc.description.sponsorshipNatural Sciences and Engineering Research Council of Canada (Postdoctoral Fellowship)en_US
dc.description.sponsorshipNational Alliance for Research on Schizophrenia and Depression (U.S.) (Young Investigator Award)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (Grant MH091115)en_US
dc.description.sponsorshipBroad Institute of MIT and Harvard. Stanley Center for Psychiatric Research (Grant)en_US
dc.language.isoen_US
dc.publisherElsevieren_US
dc.relation.isversionofhttp://dx.doi.org/10.1016/j.neuron.2011.09.030en_US
dc.rightsArticle is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.en_US
dc.sourceElsevieren_US
dc.titleCommon DISC1 Polymorphisms Disrupt Wnt/GSK3β Signaling and Brain Developmenten_US
dc.typeArticleen_US
dc.identifier.citationSingh, Karun K., Gianluca De Rienzo, Laurel Drane, Yingwei Mao, Zachary Flood, Jon Madison, Manuel Ferreira, et al. “Common DISC1 Polymorphisms Disrupt Wnt/GSK3β Signaling and Brain Development.” Neuron 72, no. 4 (November 2011): 545–558. © 2011 Elsevier Inc.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Brain and Cognitive Sciencesen_US
dc.contributor.departmentPicower Institute for Learning and Memoryen_US
dc.contributor.mitauthorSingh, Karun K.en_US
dc.contributor.mitauthorDrane, Laurelen_US
dc.contributor.mitauthorFlood, Zacharyen_US
dc.contributor.mitauthorKing, Cillianen_US
dc.contributor.mitauthorTsai, Li-Hueien_US
dc.contributor.mitauthorMao, Yingweien_US
dc.relation.journalNeuronen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsSingh, 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-Hueien_US
dc.identifier.orcidhttps://orcid.org/0000-0003-1262-0592
mit.licensePUBLISHER_POLICYen_US


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