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A Dynamic Splicing Program Ensures Proper Synaptic Connections in the Developing Cerebellum

Abstract

Tight coordination of gene expression in the developing cerebellum is crucial for establishment of neuronal circuits governing motor and cognitive function. However, transcriptional changes alone do not explain all of the switches underlying neuronal differentiation. Here we unveiled a widespread and highly dynamic splicing program that affects synaptic genes in cerebellar neurons. The motifs enriched in modulated exons implicated the splicing factor Sam68 as a regulator of this program. Sam68 controls splicing of exons with weak branchpoints by directly binding near the 3' splice site and competing with U2AF recruitment. Ablation of Sam68 disrupts splicing regulation of synaptic genes associated with neurodevelopmental diseases and impairs synaptic connections and firing of Purkinje cells, resulting in motor coordination defects, ataxia, and abnormal social behavior. These findings uncover an unexpectedly dynamic splicing regulatory network that shapes the synapse in early life and establishes motor and cognitive circuitry in the developing cerebellum.

Type Journal
ISBN 2211-1247 (Electronic)
Authors Farini, D.; Cesari, E.; Weatheritt, R. J.; La Sala, G.; Naro, C.; Pagliarini, V.; Bonvissuto, D.; Medici, V.; Guerra, M.; Di Pietro, C.; Rizzo, F. R.; Musella, A.; Carola, V.; Centonze, D.; Blencowe, B. J.; Marazziti, D.; Sette, C.
Responsible Garvan Author Robert Weatheritt
Publisher Name Cell Reports
Published Date 2020-06-02
Published Volume 31
Published Issue 9
Published Pages 107703
Status Published in-print
DOI 10.1016/j.celrep.2020.107703
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/32492419