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Lookup NU author(s): Caroline Dalgliesh, Saad Aldalaqan, Christian Atallah, Dr Andrew Best, Dr Emma ScottORCiD, Dr Ingrid Ehrmann, George Merces, Jonathan Mannion, Barbora Badurova, Dr Raveen Sandher, Dr Graham Smith, Ann HedleyORCiD, Professor Mary Herbert, Dr Colin Miles, Dr Louise Reynard, Professor David Elliott
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2025.The cellular concentrations of splicing factors (SFs) are critical for controlling alternative splicing. Most serine and arginine-enriched (SR) protein SFs regulate their own concentration via a homeostatic feedback mechanism that involves regulation of inclusion of non-coding ‘poison exons’ (PEs) that target transcripts for nonsense-mediated decay. The importance of SR protein PE splicing during animal development is largely unknown despite PE ultra-conservation across animal genomes. To address this, we used mouse genetics to disrupt an ultra-conserved PE in the Tra2b gene encoding the SR protein Tra2β. Focussing on germ cell development, we found that Tra2b PE deletion causes azoospermia due to catastrophic cell death during meiotic prophase. Failure to proceed through meiosis was associated with increased Tra2b expression sufficient to drive aberrant Tra2β protein hyper-responsive splice patterns. Although critical for meiotic prophase, Tra2b PE deletion spared earlier mitotically active germ cells, even though these still required Tra2b gene function. Our data indicate that PE splicing control prevents the accumulation of toxic levels of Tra2β protein that are incompatible with meiotic prophase. This unexpected connection with male fertility helps explain Tra2b PE ultra-conservation and indicates the importance of evaluating PE function in animal models.
Author(s): Dalgliesh C, Aldalaqan S, Atallah C, Best A, Scott E, Ehrmann I, Merces G, Mannion J, Badurova B, Sandher R, Illing Y, Wirth B, Wells S, Codner G, Teboul L, Smith GR, Hedley A, Herbert M, de Rooij DG, Miles C, Reynard LN, Elliott DJ
Publication type: Article
Publication status: Published
Journal: EMBO Journal
Year: 2025
Pages: epub ahead of print
Online publication date: 02/01/2025
Acceptance date: 04/12/2024
Date deposited: 20/01/2025
ISSN (print): 0261-4189
ISSN (electronic): 1460-2075
Publisher: EMBO Press
URL: https://doi.org/10.1038/s44318-024-00344-6
DOI: 10.1038/s44318-024-00344-6
Data Access Statement: The RNAseq and iCLIP data generated in this study is deposited in the NCBI Gene Expression Omnibus (GEO accession GSE235085). This can be accessed via the URL https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE235085. The source data of this paper are collected in the following database record: biostudies:S-SCDT-10_1038-S44318-024-00344-6.
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