A Global Regulatory Mechanism for Activating an Exon Network Required for Neurogenesis

Bushra Raj, Manuel Irimia, Ulrich Braunschweig, Timothy Sterne-Weiler, Dave O'Hanlon, Zhen-Yuan Lin, Ginny I. Chen, Laura E. Easton, Jernej Ule, Anne-Claude Gingras, Eduardo Eyras, Benjamin J. Blencowe

Research output: Contribution to journalArticlepeer-review

98 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)90-103
Number of pages14
JournalMolecular Cell
Volume56
Issue number1
DOIs
Publication statusPublished - 2 Oct 2014
Externally publishedYes

Fingerprint

Dive into the research topics of 'A Global Regulatory Mechanism for Activating an Exon Network Required for Neurogenesis'. Together they form a unique fingerprint.

Cite this