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Background <p>At present, the known genetic causes of abnormal oocyte development can only account for a minority of female infertility. In our previous study, the mutation c.1101&#xa0;C &gt; G, p.Tyr367* in discs large-associated protein 5 (<i>DLGAP5</i>) was identified as a novel genetic cause of human oocyte maturation abnormality and female infertility. The present study aimed to validate the function of DLGAP5 in oocyte maturation and further explore the underlying mechanism by which DLGAP5 regulates oocyte meiosis.</p> Results <p>Cell experiments elucidated that DLGAP5 participates in cell division, and its depletion induced G2/M arrest. The depletion of DLGAP5 in human oocytes by microinjection of siRNAs resulted in abnormal spindle morphology and oocyte maturation defects, exhibiting reduced germinal vesicle breakdown and polar body 1 extrusion rate. In addition, a similar phenotype of abnormal oocyte development was observed in <i>Dlgap5</i>-deficient mouse oocytes, which could be rescued by <i>DLGAP5</i> cRNA microinjection. Furthermore, single-cell RNA Sequencing showed <i>Dlgap5</i> knockout altered expression of genes involving in meiosis process in oocytes and deactivated PI3K-AKT signaling pathway. And PI3K-AKT activators facilitated the oocyte maturation resumption in <i>Dlgap5</i>-deficient mice.</p> Conclusions <p><i>DLGAP5</i> has been demonstrated to regulate the process of oocyte maturation via the activation of PI3K-AKT pathway. It reinforces the significant role of DLGAP5 function in oocyte maturation regulation and reveals the underlying mechanism. It provides crucial insights into clinical consultation, genetic diagnosis, and treatment strategies among infertile patients.</p>

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Loss of DLGAP5 impairs human and mouse oocyte maturation via disrupting the PI3K-AKT signaling axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月13日

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  • Meng Wang,
  • Juepu Zhou,
  • Youzhu Li,
  • Zhou Li,
  • Rui Long,
  • Xiangfei Wang,
  • Ruolin Mao,
  • Lei Xu,
  • Lei Cai,
  • Bing Han,
  • Xiyuan Dong,
  • Na Guo,
  • Huizi Jin,
  • Limin Gao,
  • Jihui Ai,
  • Qingsong Xi,
  • Lei Jin,
  • Lixia Zhu

摘要

Background

At present, the known genetic causes of abnormal oocyte development can only account for a minority of female infertility. In our previous study, the mutation c.1101 C > G, p.Tyr367* in discs large-associated protein 5 (DLGAP5) was identified as a novel genetic cause of human oocyte maturation abnormality and female infertility. The present study aimed to validate the function of DLGAP5 in oocyte maturation and further explore the underlying mechanism by which DLGAP5 regulates oocyte meiosis.

Results

Cell experiments elucidated that DLGAP5 participates in cell division, and its depletion induced G2/M arrest. The depletion of DLGAP5 in human oocytes by microinjection of siRNAs resulted in abnormal spindle morphology and oocyte maturation defects, exhibiting reduced germinal vesicle breakdown and polar body 1 extrusion rate. In addition, a similar phenotype of abnormal oocyte development was observed in Dlgap5-deficient mouse oocytes, which could be rescued by DLGAP5 cRNA microinjection. Furthermore, single-cell RNA Sequencing showed Dlgap5 knockout altered expression of genes involving in meiosis process in oocytes and deactivated PI3K-AKT signaling pathway. And PI3K-AKT activators facilitated the oocyte maturation resumption in Dlgap5-deficient mice.

Conclusions

DLGAP5 has been demonstrated to regulate the process of oocyte maturation via the activation of PI3K-AKT pathway. It reinforces the significant role of DLGAP5 function in oocyte maturation regulation and reveals the underlying mechanism. It provides crucial insights into clinical consultation, genetic diagnosis, and treatment strategies among infertile patients.