Journal
MOLECULAR CELL
Volume 72, Issue 3, Pages 510-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2018.10.008
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Funding
- EMBO
- CIHR
- OIRM
- HFSP postdoctoral fellowship
- Ontario Graduate Scholarship
- Donnelly Centre Home Fellowship
- CIHR Postdoctoral Fellowship
- SNSF fellowship
- NSERC
- Canada First Research Excellence Fund
- Simons Foundation
- Medical Research at the University of Toronto
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Alternative splicing is crucial for diverse cellular, developmental, and pathological processes. However, the full networks of factors that control individual splicing events are not known. Here, we describe a CRISPR-based strategy for the genome-wide elucidation of pathways that control splicing and apply it to microexons with important functions in nervous system development and that are commonly mis-regulated in autism. Approximately 200 genes associated with functionally diverse regulatory layers and enriched in genetic links to autism control neuronal microexons. Remarkably, the widely expressed RNA binding proteins Srsf11 and Rnps1 directly, preferentially, and frequently co-activate these microexons. These factors form critical interactions with the neuronal splicing regulator Srrm4 and a bi-partite intronic splicing enhancer element to promote spliceosome formation. Our study thus presents a versatile system for the identification of entire splicing regulatory pathways and further reveals a common mechanism for the definition of neuronal microexons that is disrupted in autism.
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