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

doi:10.1016/j.celrep.2020.107703

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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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 language	English
Pages (from-to)	107703
Journal	Cell Reports
Volume	31
Issue number	9
DOIs	https://doi.org/10.1016/j.celrep.2020.107703
Publication status	Published - Jun 2 2020

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A Dynamic Splicing ProgramFinal published version, 3.83 MBLicence: CC BY-NC-ND

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Farini, D., Cesari, E., Weatheritt, R. J., La Sala, G., Naro, C., Pagliarini, V., Bonvissuto, D., Medici, V., Guerra, M., Di Pietro, C., Rizzo, F. R., Musella, A., Carola, V., Centonze, D., Blencowe, B. J., Marazziti, D., & Sette, C. (2020). A Dynamic Splicing Program Ensures Proper Synaptic Connections in the Developing Cerebellum. Cell Reports, 31(9), 107703. https://doi.org/10.1016/j.celrep.2020.107703

Farini, D, Cesari, E, Weatheritt, RJ, La Sala, G, Naro, C, Pagliarini, V, Bonvissuto, D, Medici, V, Guerra, M, Di Pietro, C, Rizzo, FR, Musella, A, Carola, V, Centonze, D, Blencowe, BJ, Marazziti, D & Sette, C 2020, 'A Dynamic Splicing Program Ensures Proper Synaptic Connections in the Developing Cerebellum', Cell Reports, vol. 31, no. 9, pp. 107703. https://doi.org/10.1016/j.celrep.2020.107703

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title = "A Dynamic Splicing Program Ensures Proper Synaptic Connections in the Developing Cerebellum",

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.",

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

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AU - Farini, Donatella

AU - Cesari, Eleonora

AU - Weatheritt, Robert J

AU - La Sala, Gina

AU - Naro, Chiara

AU - Pagliarini, Vittoria

AU - Bonvissuto, Davide

AU - Medici, Vanessa

AU - Guerra, Marika

AU - Di Pietro, Chiara

AU - Rizzo, Francesca Romana

AU - Musella, Alessandra

AU - Carola, Valeria

AU - Centonze, Diego

AU - Blencowe, Benjamin J

AU - Marazziti, Daniela

AU - Sette, Claudio

PY - 2020/6/2

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AB - 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.

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DO - 10.1016/j.celrep.2020.107703

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VL - 31

SP - 107703

JO - Cell Reports

JF - Cell Reports

IS - 9

ER -

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

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