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

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

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)107703-N/A
JournalCell Reports
Volume31
DOIs
Publication statusPublished - 2020

Keywords

  • Sam68
  • alternative splicing
  • autism
  • cerebellum development
  • neuronal activity
  • personalized medicine
  • social behavior
  • synaptogenesis

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