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<p>Post-meiotic development of spermatids is under the control of a sophisticated RNA metabolic network, wherein the N6-methyladenosine (m<sup>6</sup>A) modification of mRNA, and proteins that bind to it, exert crucial functions in regulating sperm development from spermatogonia to spermatocytes. However, which m<sup>6</sup>A recognition proteins are involved in male post-meiotic spermiogenesis, and via which regulatory mechanisms, remains largely unknown. Here, we uncover the involvement of the m<sup>6</sup>A reader protein IGF2BP3 in the regulation of post-meiotic spermatid development. Genetic ablation of <i>Igf2bp3</i> results in spermatogenesis defects, leading to male sub-fertility or even infertility. Mechanistically, IGF2BP3 loss-of-function leads to the excessive translation of its target RNAs associated with histone-to-protamine replacement, particularly <i>Dot1l</i> and <i>Hdac11</i>. IGF2BP3 translationally represses these targets through its m<sup>6</sup>A-binding property and through its interaction with its binding partner YBX2. Sperm developmental defects of IGF2BP3 knockout mouse can be rescued by siRNAs targeting <i>Dot1l</i> and <i>Hdac11</i>. Collectively, our findings define the essential role of IGF2BP3-dependent regulation of protein biosynthesis in histone-to-protamine replacement during spermiogenesis, helping to understand the functions of m<sup>6</sup>A RNA modification in sperm development and male fertility.</p>

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IGF2BP3 recognizes m6A to regulate histone-to-protamine replacement during mouse sperm development

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月5日

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  • Dazhuang Wang,
  • Zhenyi Huang,
  • Yichun Zhou,
  • Peiyan Chen,
  • Gang Chang,
  • Liwei Ke,
  • Congying Jing,
  • Haojie Yang,
  • Jiexiang Zhao,
  • Shaofang Ren,
  • Yi Zheng,
  • Yuhan Chen,
  • Yunfan Xiang,
  • Jun Liu,
  • Mei Wang

摘要

Post-meiotic development of spermatids is under the control of a sophisticated RNA metabolic network, wherein the N6-methyladenosine (m6A) modification of mRNA, and proteins that bind to it, exert crucial functions in regulating sperm development from spermatogonia to spermatocytes. However, which m6A recognition proteins are involved in male post-meiotic spermiogenesis, and via which regulatory mechanisms, remains largely unknown. Here, we uncover the involvement of the m6A reader protein IGF2BP3 in the regulation of post-meiotic spermatid development. Genetic ablation of Igf2bp3 results in spermatogenesis defects, leading to male sub-fertility or even infertility. Mechanistically, IGF2BP3 loss-of-function leads to the excessive translation of its target RNAs associated with histone-to-protamine replacement, particularly Dot1l and Hdac11. IGF2BP3 translationally represses these targets through its m6A-binding property and through its interaction with its binding partner YBX2. Sperm developmental defects of IGF2BP3 knockout mouse can be rescued by siRNAs targeting Dot1l and Hdac11. Collectively, our findings define the essential role of IGF2BP3-dependent regulation of protein biosynthesis in histone-to-protamine replacement during spermiogenesis, helping to understand the functions of m6A RNA modification in sperm development and male fertility.