Misregulation of an activity-dependent splicing network as a common mechanism underlying autism spectrum disorders

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• dc.contributor.author Quesnel-Vallières, Mathieu
• dc.contributor.author Dargaei, Zahra
• dc.contributor.author Irimia Martínez, Manuel
• dc.contributor.author Gonatopoulos-Pournatzis, Thomas
• dc.contributor.author Ip, Joanna Y.
• dc.contributor.author Wu, Mingkun
• dc.contributor.author Sterne-Weiler, Thimothy
• dc.contributor.author Nakagawa, Shinichi
• dc.contributor.author Woodin, Melanie A.
• dc.contributor.author Blencowe, Benjamin J.
• dc.contributor.author Cordes, Sabine P.
• dc.date.accessioned 2021-05-03T07:45:14Z
• dc.date.available 2021-05-03T07:45:14Z
• dc.date.issued 2016
• dc.description.abstract A key challenge in understanding and ultimately treating autism is to identify common molecular mechanisms underlying this genetically heterogeneous disorder. Transcriptomic profiling of autistic brains has revealed correlated misregulation of the neuronal splicing regulator nSR100/SRRM4 and its target microexon splicing program in more than one-third of analyzed individuals. To investigate whether nSR100 misregulation is causally linked to autism, we generated mutant mice with reduced levels of this protein and its target splicing program. Remarkably, these mice display multiple autistic-like features, including altered social behaviors, synaptic density, and signaling. Moreover, increased neuronal activity, which is often associated with autism, results in a rapid decrease in nSR100 and splicing of microexons that significantly overlap those misregulated in autistic brains. Collectively, our results provide evidence that misregulation of an nSR100-dependent splicing network controlled by changes in neuronal activity is causally linked to a substantial fraction of autism cases.
• dc.description.sponsorship This work was supported by CIHR grants to S.P.C. (MOP#111199 and MOP#142340), B.J.B. (MOP#14609 and FDN#148434), and M.A.W.(MOP#12346), and an ERC Starting Grant to M.I. (ERC-StG-LS2-637591). M.Q.V. was supported by CIHR and OGS scholarships. T.G.-P. was supported by EMBO and OIRM fellowships
• dc.format.mimetype application/pdf
• dc.identifier.citation Quesnel-Vallières M, Dargaei Z, Irima M, Gonatopoulos-Pournatzis T, Ip JY, Wu M et al. Misregulation of an activity-dependent splicing network as a common mechanism underlying autism spectrum disorders. Mol Cell. 2016 Dec 15;64(6):1023-1034. DOI: 10.1016/j.molcel.2016.11.033
• dc.identifier.doi http://dx.doi.org/10.1016/j.molcel.2016.11.033
• dc.identifier.issn 1097-2765
• dc.identifier.uri http://hdl.handle.net/10230/47277
• dc.language.iso eng
• dc.publisher Elsevier
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/637591
• dc.rights © Elsevier 2016 Inc. Under an Elsevier user license
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.subject.other Autisme
• dc.subject.other Genètica
• dc.subject.other Neurologia
• dc.title Misregulation of an activity-dependent splicing network as a common mechanism underlying autism spectrum disorders
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion