title: Essential roles for the splicing regulator nSR100/SRRM4 during nervous system development.
abstract: Alternative splicing (AS) generates vast transcriptomic complexity in the vertebrate nervous system. However, the extent to which trans-acting splicing regulators and their target AS regulatory networks contribute to nervous system development is not well understood. To address these questions, we generated mice lacking the vertebrate- and neural-specific Ser/Arg repeat-related protein of 100 kDa (nSR100/SRRM4). Loss of nSR100 impairs development of the central and peripheral nervous systems in part by disrupting neurite outgrowth, cortical layering in the forebrain, and axon guidance in the corpus callosum. Accompanying these developmental defects are widespread changes in AS that primarily result in shifts to nonneural patterns for different classes of splicing events. The main component of the altered AS program comprises 3- to 27-nucleotide (nt) neural microexons, an emerging class of highly conserved AS events associated with the regulation of protein interaction networks in developing neurons and neurological disorders. Remarkably, inclusion of a 6-nt, nSR100-activated microexon in Unc13b transcripts is sufficient to rescue a neuritogenesis defect in nSR100 mutant primary neurons. These results thus reveal critical in vivo neurodevelopmental functions of nSR100 and further link these functions to a conserved program of neuronal microexon splicing.
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Quesnel-Vallières
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada;
authors.forename: Manuel
authors.initials: M
authors.lastname: Irimia
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada b.blencowe@utoronto.ca cordes@lunenfeld.ca.
authors.forename: Sabine P
authors.initials: SP
authors.lastname: Cordes
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada; b.blencowe@utoronto.ca cordes@lunenfeld.ca.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Blencowe
mesh_terms: D000818:Animals; D004622:Embryo, Mammalian; D005091:Exons / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009420:Nervous System / Q000196:embryology*; D055495:Neurogenesis / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics*; D017423:Sequence Analysis, RNA
chemical_list: D009419:Nerve Tissue Proteins; C543899:nSR100 protein, mouse
keywords: SR proteins; alternative splicing; microexons; nervous system development
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