title: Misregulation of an Activity-Dependent Splicing Network as a Common Mechanism Underlying Autism Spectrum Disorders.
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.
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Quesnel-Vallières
authors.affiliation: Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Dargaei
authors.affiliation: Centre for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), Dr. Aiguader 88, Barcelona 08003, Spain; Universitat Pompeu Fabra, Barcelona 08002, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Irimia
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gonatopoulos-Pournatzis
authors.affiliation: RNA Biology Laboratory, RIKEN, Wako, Saitama 351-0198, Japan.
authors.forename: Joanna Y
authors.initials: JY
authors.lastname: Ip
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors.forename: Mingkun
authors.initials: M
authors.lastname: Wu
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors.forename: Timothy
authors.initials: T
authors.lastname: Sterne-Weiler
authors.affiliation: RNA Biology Laboratory, RIKEN, Wako, Saitama 351-0198, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Nakagawa
authors.affiliation: Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada.
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Woodin
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada. Electronic address: b.blencowe@utoronto.ca.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Blencowe
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada. Electronic address: cordes@lunenfeld.ca.
authors.forename: Sabine P
authors.initials: SP
authors.lastname: Cordes
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005091:Exons; D005260:Female; D015870:Gene Expression; D057895:Haploinsufficiency; D006801:Humans; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D013216:Reflex, Startle; D009435:Synaptic Transmission
chemical_list: D009419:Nerve Tissue Proteins; C000595377:SRRM4 protein, human; C543899:nSR100 protein, mouse
keywords: alternative splicing; autism spectrum disorder; microexons; nSR100/SRRM4; neuronal activity