title: Alternative splicing coupled nonsense-mediated decay generates neuronal cell type-specific expression of SLM proteins.
abstract: The unique physiological and morphological properties of neuronal populations are crucial for the appropriate functioning of neuronal circuits. Alternative splicing represents an attractive mechanism for generating cell type-specific molecular repertoires that steer neuronal development and function. However, the mechanisms that link neuronal identity to alternative splicing programs are poorly understood. We report that cell type-specific, mutually exclusive expression of two alternative splicing regulators, SLM1 and SLM2, in the mouse hippocampus is achieved by a cross-repression mechanism. Deletion of SLM2 in vivo modifies alternative splicing of its paralog Slm1 and stabilizes its mRNA, resulting in expression of SLM1 in previously SLM2-expressing cells. Despite this ectopic upregulation of SLM1, loss of SLM2 severely disrupts the alternative splicing regulation of Nrxn1, Nrxn2, and Nrxn3, highlighting that the two SLM paralogs have partially divergent functions. Our study uncovers a hierarchical, SLM2-dependent mechanism for establishing cell type-specific expression of neuronal splicing regulators in vivo.
authors.affiliation: Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Lisa
authors.initials: L
authors.lastname: Traunmüller
authors.affiliation: Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Caroline
authors.initials: C
authors.lastname: Bornmann
authors.affiliation: Biozentrum, University of Basel, 4056 Basel, Switzerland peter.scheiffele@unibas.ch.
authors.forename: Peter
authors.identifier: http://orcid.org/0000-0002-9516-9399
authors.initials: P
authors.lastname: Scheiffele
mesh_terms: D017398:Alternative Splicing / Q000502:physiology*; D000818:Animals; D005260:Female; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D059365:Nonsense Mediated mRNA Decay / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000096:biosynthesis*
chemical_list: C118776:Khdrbs2 protein, mouse; C486528:Khdrbs3 protein, mouse; D016601:RNA-Binding Proteins
keywords: Cbln; RNA; alternative splicing; neurexin; neuroligin; plasticity