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Differential expression of paralog RNA binding proteins establishes a dynamic splicing program required for normal cerebral cortex development

Lookup NU author(s): Dr Ingrid Ehrmann, Professor David Elliott

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Abstract

© 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.

Publication metadata

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

PubMed id: 38324473

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