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

• Published in: Cell reports (Cambridge) 2020-06, Vol.31 (9), p.107703-107703, Article 107703
• Main Authors: Farini, Donatella, Cesari, Eleonora, Weatheritt, Robert J., La Sala, Gina, Naro, Chiara, Pagliarini, Vittoria, Bonvissuto, Davide, Medici, Vanessa, Guerra, Marika, Di Pietro, Chiara, Rizzo, Francesca Romana, Musella, Alessandra, Carola, Valeria, Centonze, Diego, Blencowe, Benjamin J., Marazziti, Daniela, Sette, Claudio
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - deficiency; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; alternative splicing; Animals; autism; Behavior, Animal; Cerebellum - cytology; Cerebellum - growth & development; Cerebellum - metabolism; cerebellum development; Female; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; neuronal activity; personalized medicine; Protein Binding; Purkinje Cells - metabolism; RNA Splice Sites; RNA Splicing; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Sam68; social behavior; Splicing Factor U2AF - metabolism; Synapses - metabolism; synaptogenesis
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.107703

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. [Display omitted] •A dynamic splicing program shapes the cerebellar transcriptome during development•Autism-spectrum-disorder-related genes exhibit developmental splicing regulation•Sam68 establishes a splicing signature that ensures proper synaptic maturation•Sam68 regulates genes associated with autism spectrum disorder and social behavior Alternative splicing contributes to all steps of brain development. Farini et al. show that maturation of the cerebellum involves a dynamic splicing program that mainly affects synaptic genes. Precocious dysregulation of this program by Sam68 ablation alters cerebellar neuronal connectivity and results in defective motor coordination and social behavior.