An ultra-conserved poison exon in the Tra2b gene encoding a splicing activator is essential for male fertility and meiotic cell division

Caroline Dalgliesh, Saad Aldalaqan, Christian Atallah, Andrew Best, Emma Scott, Ingrid Ehrmann, George Merces, Joel Mannion, Barbora Badurova, Raveen Sandher, Ylva Illing, Brunhilde Wirth, Sara Wells, Gemma Codner, Lydia Teboul, Graham R. Smith, Ann Hedley, Mary Herbert, Dirk G. de Rooij, Colin MilesLouise N. Reynard, David J. Elliott*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Article number4760
Pages (from-to)877-902
JournalEMBO Journal
Volume44
Issue number3
Early online date2 Jan 2025
DOIs
Publication statusPublished - 3 Feb 2025

Bibliographical note

Publisher Copyright:
© The Author(s) 2025.

Funding

The work in this report was funded by the Biological and Biotechnological Research Council (BBSRC) grants BB/I006923/1, BB/S008039/1 and BB/W002019/1 and the King Fahad Medical City, Ministry of Health, Kingdom of Saudi Arabia. The Mary Lyon Centre at MRC Harwell delivered the C57BL/6J-Tra2bem1H/H mouse strain as part of its commitment to the Genome Editing Mice for Medicine project funded by the Medical Research Council grant MC_UP_2201/2. RNAseq was carried out by Newcastle University Genomics Core Facility. The authors thank Veronika Boczonadi of the Newcastle University BioImaging Unit for her support & assistance in this work.

FundersFunder number
UKRI | Biotechnology and Biological Sciences Research Council (BBSRC)BB/I006923/1, BB/S008039/1, BB/W002019/1
Biological and Biotechnological Research Council (BBSRC)
King Fahad Medical City, Ministry of Health, Kingdom of Saudi ArabiaMC_UP_2201/2
Mary Lyon Centre at MRC Harwell - Medical Research Council

    Keywords

    • Alternative Splicing
    • Fertility
    • Poison Exon
    • Spermatogenesis
    • Ultraconserved Genome Sequence

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