Scholarlink

<p>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 <i>Tra2b</i> gene encoding the SR protein Tra2β. Focussing on germ cell development, we found that <i>Tra2b</i> PE deletion causes azoospermia due to catastrophic cell death during meiotic prophase. Failure to proceed through meiosis was associated with increased <i>Tra2b</i> expression sufficient to drive aberrant Tra2β protein hyper-responsive splice patterns. Although critical for meiotic prophase, <i>Tra2b</i> PE deletion spared earlier mitotically active germ cells, even though these still required <i>Tra2b</i> 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 <i>Tra2b</i> PE ultra-conservation and indicates the importance of evaluating PE function in animal models.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年1月2日

查看全文
  • 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 Miles,
  • Louise N Reynard,
  • David J Elliott

摘要

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.