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
Affiliations
Donatella Farini
Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy; Fondazione Santa Lucia, IRCCS, Rome, Italy
Eleonora Cesari
Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, Rome, Italy; Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy
Robert J. Weatheritt
Donnelly Centre and Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; EMBL Australia, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
Gina La Sala
Institute of Cell Biology and Neurobiology, CNR, Monterotondo, Rome, Italy
Chiara Naro
Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, Rome, Italy; Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy
Vittoria Pagliarini
Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, Rome, Italy; Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy
Davide Bonvissuto
Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, Rome, Italy
Vanessa Medici
Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy; Fondazione Santa Lucia, IRCCS, Rome, Italy
Marika Guerra
Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, Rome, Italy; Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy
Chiara Di Pietro
Institute of Cell Biology and Neurobiology, CNR, Monterotondo, Rome, Italy
Francesca Romana Rizzo
Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; San Raffaele Pisana and University San Raffaele, IRCCS, Rome, Italy
Alessandra Musella
San Raffaele Pisana and University San Raffaele, IRCCS, Rome, Italy
Valeria Carola
Fondazione Santa Lucia, IRCCS, Rome, Italy; Department of Dynamic and Clinical Psychology, University of Rome Sapienza, Rome, Italy
Diego Centonze
Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; Unit of Neurology, IRCCS Neuromed, Pozzilli, Isernia, Italy
Benjamin J. Blencowe
Donnelly Centre and Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
Daniela Marazziti
Institute of Cell Biology and Neurobiology, CNR, Monterotondo, Rome, Italy
Claudio Sette
Fondazione Santa Lucia, IRCCS, Rome, Italy; Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, Rome, Italy; Corresponding author
Summary: 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.
