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

Donatella Farini, Eleonora Cesari, Robert J Weatheritt, Gina La Sala, Chiara Naro, Vittoria Pagliarini, Davide Bonvissuto, Vanessa Medici, Marika Guerra, Chiara Di Pietro, Francesca Romana Rizzo, Alessandra Musella, Valeria Carola, Diego Centonze, Benjamin J Blencowe, Daniela Marazziti, Claudio Sette

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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.

Original languageEnglish
Pages (from-to)107703
JournalCell Reports
Issue number9
Publication statusPublished - Jun 2 2020


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