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<p>Alternative splicing (AS) events are exceptionally active during spermatogenesis, enhancing the diversity of the testicular transcriptome and proteome. In mouse testes, the germ cell-specific RNA-binding protein DAZL undergoes alternative splicing to produce two isoforms: a full-length DAZL (DAZL_FL) and a short isoform lacking exon 8 (DAZL_Sh). While DAZL is a hallmark of germ cell development, the physiological roles of its alternative splicing, and the distinct functions of these two isoforms remain yet to be fully elucidated. To investigate this, we disrupted alternative splicing of <i>Dazl</i> by generating DAZL short isoform only mice via deletion of the DAZL exon 8 and found that the resulting loss of DAZL_FL led to male infertility, characterized by extensive spermatocyte apoptosis and arrest of spermatid development. Ribosome profiling (Ribo-seq) revealed that loss of DAZL_FL downregulated the translation of meiotic genes specifically bound by DAZL. Mechanistically, DAZL_Sh failed to interact with Poly(A) Binding Protein Cytoplasmic 1 (PABPC1), resulting in impaired translation of DAZL-targeted germ cell transcripts. In females, DAZL_FL ablation caused complete infertility, marked by massive primordial follicle apoptosis and failure of primary follicle recruitment, highlighting a shared role for DAZL_FL in meiotic regulation in both sexes. Our findings established DAZL/PABPC1 complex formation as a pivotal mechanism controlling meiotic progression. By functionally dissecting DAZL isoforms, we uncovered a critical role of <i>Dazl</i> alternative splicing during spermatogenesis and folliculogenesis, further expanding the roles of DAZL in germ cell development and thereby providing novel genetic causes and potential therapeutic targets for azoospermia and primary ovarian insufficiency.</p>

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Loss of full-length DAZL isoform disrupts PABPC1-dependent translational regulation and meiosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月17日

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  • Xin Li,
  • Dandan Cao,
  • Yue Lu,
  • Zexin Bian,
  • Tingting Zhao,
  • Wenbo Liu,
  • Yan Zhao,
  • Jun Tan,
  • Lei Li,
  • Eugene Yujun Xu

摘要

Alternative splicing (AS) events are exceptionally active during spermatogenesis, enhancing the diversity of the testicular transcriptome and proteome. In mouse testes, the germ cell-specific RNA-binding protein DAZL undergoes alternative splicing to produce two isoforms: a full-length DAZL (DAZL_FL) and a short isoform lacking exon 8 (DAZL_Sh). While DAZL is a hallmark of germ cell development, the physiological roles of its alternative splicing, and the distinct functions of these two isoforms remain yet to be fully elucidated. To investigate this, we disrupted alternative splicing of Dazl by generating DAZL short isoform only mice via deletion of the DAZL exon 8 and found that the resulting loss of DAZL_FL led to male infertility, characterized by extensive spermatocyte apoptosis and arrest of spermatid development. Ribosome profiling (Ribo-seq) revealed that loss of DAZL_FL downregulated the translation of meiotic genes specifically bound by DAZL. Mechanistically, DAZL_Sh failed to interact with Poly(A) Binding Protein Cytoplasmic 1 (PABPC1), resulting in impaired translation of DAZL-targeted germ cell transcripts. In females, DAZL_FL ablation caused complete infertility, marked by massive primordial follicle apoptosis and failure of primary follicle recruitment, highlighting a shared role for DAZL_FL in meiotic regulation in both sexes. Our findings established DAZL/PABPC1 complex formation as a pivotal mechanism controlling meiotic progression. By functionally dissecting DAZL isoforms, we uncovered a critical role of Dazl alternative splicing during spermatogenesis and folliculogenesis, further expanding the roles of DAZL in germ cell development and thereby providing novel genetic causes and potential therapeutic targets for azoospermia and primary ovarian insufficiency.