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

Author

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, and Sette C

Subjects
Adaptor Proteins, Signal Transducing deficiency, Adaptor Proteins, Signal Transducing genetics, Animals, Behavior, Animal, Cerebellum cytology, Cerebellum growth & development, Female, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Protein Binding, Purkinje Cells metabolism, RNA Splice Sites, RNA-Binding Proteins genetics, Splicing Factor U2AF metabolism, Adaptor Proteins, Signal Transducing metabolism, Cerebellum metabolism, RNA Splicing, RNA-Binding Proteins metabolism, Synapses metabolism
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., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2020
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2. A SLM2 Feedback Pathway Controls Cortical Network Activity and Mouse Behavior.

Author

Ehrmann I, Gazzara MR, Pagliarini V, Dalgliesh C, Kheirollahi-Chadegani M, Xu Y, Cesari E, Danilenko M, Maclennan M, Lowdon K, Vogel T, Keskivali-Bond P, Wells S, Cater H, Fort P, Santibanez-Koref M, Middei S, Sette C, Clowry GJ, Barash Y, Cunningham MO, and Elliott DJ

Subjects
Adaptor Proteins, Signal Transducing genetics, Animals, Behavior, Animal physiology, Calcium-Binding Proteins, Homeostasis genetics, Mice, Mice, Knockout, Neural Cell Adhesion Molecules genetics, RNA Precursors genetics, RNA-Binding Proteins metabolism, Synapses physiology, Alternative Splicing genetics, Nerve Net, Pyramidal Cells metabolism, RNA-Binding Proteins genetics, Synapses genetics
Abstract

The brain is made up of trillions of synaptic connections that together form neural networks needed for normal brain function and behavior. SLM2 is a member of a conserved family of RNA binding proteins, including Sam68 and SLM1, that control splicing of Neurexin1-3 pre-mRNAs. Whether SLM2 affects neural network activity is unknown. Here, we find that SLM2 levels are maintained by a homeostatic feedback control pathway that predates the divergence of SLM2 and Sam68. SLM2 also controls the splicing of Tomosyn2, LysoPLD/ATX, Dgkb, Kif21a, and Cask, each of which are important for synapse function. Cortical neural network activity dependent on synaptic connections between SLM2-expressing-pyramidal neurons and interneurons is decreased in Slm2-null mice. Additionally, these mice are anxious and have a decreased ability to recognize novel objects. Our data reveal a pathway of SLM2 homeostatic auto-regulation controlling brain network activity and behavior., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2016
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