Journal
MOLECULAR CELL
Volume 56, Issue 1, Pages 90-103Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2014.08.011
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Funding
- Canadian Institutes of Health Research
- ORF
- Natural Sciences and Engineering Research Council of Canada (NSERC) Polyani Award
- Spanish Government
- Sandra Ibarra Foundation for Cancer
- NSERC
- University of Toronto
- Human Frontiers Science Program Organization
- EMBO
- [BIO2011-23920]
- [CSD2009-00080]
- ICREA Funding Source: Custom
- Medical Research Council [MC_U105185858, MC_U105178934] Funding Source: researchfish
- MRC [MC_U105185858, MC_U105178934] Funding Source: UKRI
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The vertebrate and neural-specific Ser/Arg (SR)related protein nSR100/SRRM4 regulates an extensive program of alternative splicing with critical roles in nervous system development. However, the mechanism by which nSR100 controls its target exons is poorly understood. We demonstrate that nSR100-dependent neural exons are associated with a unique configuration of intronic cis-elements that promote rapid switch-like regulation during neurogenesis. A key feature of this configuration is the insertion of specialized intronic enhancers between polypyrimidine tracts and acceptor sites that bind nSR100 to potently activate exon inclusion in neural cells while weakening 30 splice site recognition and contributing to exon skipping in nonneural cells. nSR100 further operates by forming multiple interactions with early spliceosome components bound proximal to 30 splice sites. These multifaceted interactions achieve dominance over neural exon silencing mediated by the splicing regulator PTBP1. The results thus illuminate a widespread mechanism by which a critical neural exon network is activated during neurogenesis.
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