title: A highly conserved program of neuronal microexons is misregulated in autistic brains.
abstract: Alternative splicing (AS) generates vast transcriptomic and proteomic complexity. However, which of the myriad of detected AS events provide important biological functions is not well understood. Here, we define the largest program of functionally coordinated, neural-regulated AS described to date in mammals. Relative to all other types of AS within this program, 3-15 nucleotide "microexons" display the most striking evolutionary conservation and switch-like regulation. These microexons modulate the function of interaction domains of proteins involved in neurogenesis. Most neural microexons are regulated by the neuronal-specific splicing factor nSR100/SRRM4, through its binding to adjacent intronic enhancer motifs. Neural microexons are frequently misregulated in the brains of individuals with autism spectrum disorder, and this misregulation is associated with reduced levels of nSR100. The results thus reveal a highly conserved program of dynamic microexon regulation associated with the remodeling of protein-interaction networks during neurogenesis, the misregulation of which is linked to autism.
authors.affiliation: Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada; EMBL/CRG Research Unit in Systems Biology, Centre for Genomic Regulation (CRG), 88 Dr. Aiguader, Barcelona 08003, Spain. Electronic address: mirimia@gmail.com.
authors.forename: Manuel
authors.initials: M
authors.lastname: Irimia
authors.affiliation: Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada; MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Weatheritt
authors.affiliation: Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Ellis
authors.affiliation: Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA.
authors.forename: Neelroop N
authors.initials: NN
authors.lastname: Parikshak
authors.affiliation: Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gonatopoulos-Pournatzis
authors.affiliation: Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada.
authors.forename: Mariana
authors.initials: M
authors.lastname: Babor
authors.affiliation: Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Quesnel-Vallières
authors.affiliation: EMBL/CRG Research Unit in Systems Biology, Centre for Genomic Regulation (CRG), 88 Dr. Aiguader, Barcelona 08003, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Tapial
authors.affiliation: Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada.
authors.forename: Bushra
authors.initials: B
authors.lastname: Raj
authors.affiliation: Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada.
authors.forename: Dave
authors.initials: D
authors.lastname: O'Hanlon
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada.
authors.forename: Miriam
authors.initials: M
authors.lastname: Barrios-Rodiles
authors.affiliation: Centre for Integrative Systems Biology and Bioinformatics, Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
authors.forename: Michael J E
authors.initials: MJ
authors.lastname: Sternberg
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors.forename: Sabine P
authors.initials: SP
authors.lastname: Cordes
authors.affiliation: Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Department of Computer Science, University of Toronto, 10 King's College Road, Toronto, ON M5S 3G4, Canada; Canadian Institute For Advanced Research, 180 Dundas Street West, Toronto, ON M5G 1Z8, Canada.
authors.forename: Frederick P
authors.initials: FP
authors.lastname: Roth
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Wrana
authors.affiliation: Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
authors.affiliation: Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada. Electronic address: b.blencowe@utoronto.ca.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Blencowe
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D002659:Child Development Disorders, Pervasive / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D055495:Neurogenesis; D009474:Neurons / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D017423:Sequence Analysis, RNA; D013702:Temporal Lobe / Q000473:pathology
chemical_list: D009419:Nerve Tissue Proteins; C000595377:SRRM4 protein, human