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 language | English |
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Article number | 4760 |
Pages (from-to) | 877-902 |
Journal | EMBO Journal |
Volume | 44 |
Issue number | 3 |
Early online date | 2 Jan 2025 |
DOIs | |
Publication status | Published - 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.
Funders | Funder number |
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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 Arabia | MC_UP_2201/2 |
Mary Lyon Centre at MRC Harwell - Medical Research Council |
Keywords
- Alternative Splicing
- Fertility
- Poison Exon
- Spermatogenesis
- Ultraconserved Genome Sequence