title: SAM68 regulates neuronal activity-dependent alternative splicing of neurexin-1.
abstract: The assembly of synapses and neuronal circuits relies on an array of molecular recognition events and their modification by neuronal activity. Neurexins are a highly polymorphic family of synaptic receptors diversified by extensive alternative splicing. Neurexin variants exhibit distinct isoform-specific biochemical interactions and synapse assembly functions, but the mechanisms governing splice isoform choice are not understood. We demonstrate that Nrxn1 alternative splicing is temporally and spatially controlled in the mouse brain. Neuronal activity triggers a shift in Nrxn1 splice isoform choice via calcium/calmodulin-dependent kinase IV signaling. Activity-dependent alternative splicing of Nrxn1 requires the KH-domain RNA-binding protein SAM68 that associates with RNA response elements in the Nrxn1 pre-mRNA. Our findings uncover SAM68 as a key regulator of dynamic control of Nrxn1 molecular diversity and activity-dependent alternative splicing in the central nervous system.
authors.affiliation: Biozentrum, University of Basel, Klingelbergstrasse 50-70, 4056 Basel, Switzerland.
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Iijima
authors.forename: Karen
authors.initials: K
authors.lastname: Wu
authors.forename: Harald
authors.initials: H
authors.lastname: Witte
authors.forename: Yoko
authors.initials: Y
authors.lastname: Hanno-Iijima
authors.forename: Timo
authors.initials: T
authors.lastname: Glatter
authors.forename: Stéphane
authors.initials: S
authors.lastname: Richard
authors.forename: Peter
authors.initials: P
authors.lastname: Scheiffele
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D002135:Calcium-Binding Proteins; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C513253:Khdrbs1 protein, mouse; D019006:Neural Cell Adhesion Molecules; C527193:Nrxn1 protein, mouse; D016601:RNA-Binding Proteins