title: Cross-regulation between an alternative splicing activator and a transcription repressor controls neurogenesis.
abstract: Neurogenesis requires the concerted action of numerous genes that are regulated at multiple levels. However, how different layers of gene regulation are coordinated to promote neurogenesis is not well understood. We show that the neural-specific Ser/Arg repeat-related protein of 100 kDa (nSR100/SRRM4) negatively regulates REST (NRSF), a transcriptional repressor of genes required for neurogenesis. nSR100 directly promotes alternative splicing of REST transcripts to produce a REST isoform (REST4) with greatly reduced repressive activity, thereby activating expression of REST targets in neural cells. Conversely, REST directly represses nSR100 in nonneural cells to prevent the activation of neural-specific splicing events. Consistent with a critical role for nSR100 in the inhibition of REST activity, blocking nSR100 expression in the developing mouse brain impairs neurogenesis. Our results thus reveal a fundamental role for direct regulatory interactions between a splicing activator and transcription repressor in the control of the multilayered regulatory programs required for neurogenesis.
authors: Banting and Best Department of Medical Research, Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada.
authors: Bushra
authors: B
authors: Raj
authors: Dave
authors: D
authors: O'Hanlon
authors: John P
authors: JP
authors: Vessey
authors: Qun
authors: Q
authors: Pan
authors: Debashish
authors: D
authors: Ray
authors: Noel J
authors: NJ
authors: Buckley
authors: Freda D
authors: FD
authors: Miller
authors: Benjamin J
authors: BJ
authors: Blencowe
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D002478:Cells, Cultured; D051379:Mice; D008815:Mice, Inbred Strains; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012326:RNA Splicing; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D000099229:RE1-Silencing Transcription Factor
chemical_list: D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D012097:Repressor Proteins; D014157:Transcription Factors; D000099229:RE1-Silencing Transcription Factor; C543899:nSR100 protein, mouse