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Lookup NU author(s): Dr Ingrid Ehrmann, Professor David Elliott
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research. Sam68 and SLM2 are paralog RNA binding proteins (RBPs) expressed in the cerebral cortex and display similar splicing activities. However, their relative functions during cortical development are unknown. We found that these RBPs exhibit an opposite expression pattern during development. Sam68 expression declines postnatally while SLM2 increases after birth, and this developmental pattern is reinforced by hierarchical control of Sam68 expression by SLM2. Analysis of Sam68:Slm2 double knockout (Sam68:Slm2dko) mice revealed hundreds of exons that respond to joint depletion of these proteins. Moreover, parallel analysis of single and double knockout cortices indicated that exons regulated mainly by SLM2 are characterized by a dynamic splicing pattern during development, whereas Sam68-dependent exons are spliced at relatively constant rates. Dynamic splicing of SLM2-sensitive exons is completely suppressed in the Sam68:Slm2dko developing cortex. Sam68:Slm2dko mice die perinatally with defects in neurogenesis and in neuronal differentiation, and develop a hydrocephalus, consistent with splicing alterations in genes related to these biological processes. Thus, our study reveals that developmental control of separate Sam68 and Slm2 paralog genes encoding homologous RBPs enables the orchestration of a dynamic splicing program needed for brain development and viability, while ensuring a robust redundant mechanism that supports proper cortical development.
Author(s): Cesari E, Farini D, Medici V, Ehrmann I, Guerra M, Testa E, Naro C, Geloso MC, Pagliarini V, La Barbera L, D'Amelio M, Orsini T, Vecchioli SF, Tamagnone L, Fort P, Viscomi MT, Elliott DJ, Sette C
Publication type: Article
Publication status: Published
Journal: Nucleic Acids Research
Year: 2024
Volume: 52
Issue: 8
Pages: 4167-4184
Print publication date: 08/05/2024
Online publication date: 07/02/2024
Acceptance date: 25/01/2024
Date deposited: 20/05/2024
ISSN (print): 0305-1048
ISSN (electronic): 1362-4962
Publisher: Oxford University Press
URL: https://doi.org/10.1093/nar/gkae071
DOI: 10.1093/nar/gkae071
Data Access Statement: All data generated or analyzed during this study are included in this article. The RNA sequencing data are available in Gene Expression Omnibus under accession number GSE229749.
PubMed id: 38324473
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