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Loss of DLGAP5 impairs human and mouse oocyte maturation via disrupting the PI3K-AKT signaling axis
Meng Wang1, Juepu Zhou1, Youzhu Li2,3
1Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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.
Insights
Discs large-associated protein 5 (DLGAP5) is crucial for female fertility. Its deficiency causes oocyte maturation defects by disrupting meiosis and the PI3K-AKT pathway, offering insights for treating infertility.
Area of Science:
- Reproductive biology
- Molecular genetics
- Cell biology
Background:
- Genetic factors for abnormal oocyte development explain limited female infertility cases.
- A prior study identified a DLGAP5 mutation as a novel cause of oocyte maturation abnormality and infertility.
Purpose of the Study:
- To validate DLGAP5's function in oocyte maturation.
- To explore the mechanism of DLGAP5 in regulating oocyte meiosis.
Main Methods:
- Cell experiments and siRNA microinjection in human oocytes.
- Analysis of Dlgap5-deficient mouse oocytes.
- Single-cell RNA sequencing (scRNA-seq).
- PI3K-AKT pathway activation.
Main Results:
- DLGAP5 depletion caused G2/M arrest and impaired oocyte maturation, including reduced germinal vesicle breakdown and polar body extrusion.
- Dlgap5 deficiency in mice phenocopied these defects, which were reversible.
- scRNA-seq revealed altered meiotic gene expression and PI3K-AKT pathway deactivation in Dlgap5-deficient oocytes.
- PI3K-AKT activators rescued oocyte maturation in Dlgap5-deficient mice.
Conclusions:
- DLGAP5 regulates oocyte maturation through PI3K-AKT pathway activation.
- This highlights DLGAP5's critical role in oocyte maturation and provides mechanistic insights.
- Findings aid clinical consultation, genetic diagnosis, and treatment for infertility.
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