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.

A Dynamic Splicing Program Ensures Proper Synaptic Connections in the Developing Cerebellum / Farini, Donatella; Cesari, Eleonora; J Weatheritt, Robert; La Sala Chiara Naro, Gina; Pagliarini, Vittoria; Bonvissuto, Davide; Medici, Vanessa; Guerra, Marika; DI PIETRO, Chiara; Romana Rizzo Alessandra Musella, Francesca; Carola, Valeria; Centonze, Diego; J Blencowe, Benjamin; Marazziti, Daniela; Sette, Claudio. - In: CELL REPORTS. - ISSN 2211-1247. - (2020). [10.1016/j.celrep.2020.107703]

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

Davide Bonvissuto;Chiara Di Pietro;Valeria Carola
Methodology
;
2020

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.
2020
Sam68; alternative splicing; autism; cerebellum development; neuronal activity; personalized medicine; social behavior; synaptogenesis.
01 Pubblicazione su rivista::01a Articolo in rivista
A Dynamic Splicing Program Ensures Proper Synaptic Connections in the Developing Cerebellum / Farini, Donatella; Cesari, Eleonora; J Weatheritt, Robert; La Sala Chiara Naro, Gina; Pagliarini, Vittoria; Bonvissuto, Davide; Medici, Vanessa; Guerra, Marika; DI PIETRO, Chiara; Romana Rizzo Alessandra Musella, Francesca; Carola, Valeria; Centonze, Diego; J Blencowe, Benjamin; Marazziti, Daniela; Sette, Claudio. - In: CELL REPORTS. - ISSN 2211-1247. - (2020). [10.1016/j.celrep.2020.107703]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1406861
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