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ARHGAP26 deficiency drives the oocyte aneuploidy and early embryonic development failure

Cell Death & Differentiation (2024)Cite this article

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Abstract

Aneuploidy, the presence of a chromosomal anomaly, is a major cause of spontaneous abortions and recurrent pregnancy loss in humans. However, the underlying molecular mechanisms still remain poorly understood. Here, we report that ARHGAP26, a putative tumor suppressor gene, is a newly identified regulator of oocyte quality to maintain mitochondrial integrity and chromosome euploidy, thus ensuring normal embryonic development and fertility. Taking advantage of knockout mouse model, we revealed that genetic ablation of Arhgap26 caused the oocyte death at GV stage due to the mitochondrial dysfunction-induced ROS accumulation. Lack of Arhgap26 also impaired both in vitro and in vivo maturation of survived oocytes which results in maturation arrest and aneuploidy, and consequently leading to early embryonic development defects and subfertility. These observations were further verified by transcriptome analysis. Mechanistically, we discovered that Arhgap26 interacted with Cofilin1 to maintain the mitochondrial integrity by regulating Drp1 dynamics, and restoration of Arhgap26 protein level recovered the quality of Arhgap26-null oocytes. Importantly, we found an ARHGAP26 mutation in a patient with history of recurrent miscarriage by chromosomal microarray analysis. Altogether, our findings uncover a novel function of ARHGAP26 in the oocyte quality control and prevention of aneuploidy and provide a potential treatment strategy for infertile women caused by ARHGAP26 mutation.

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Fig. 1: Effects of Arhgap26 deletion on the quality of mouse GV oocytes.
Fig. 2: Effects of Arhgap26 deletion on the mouse oocyte maturation in vitro.
Fig. 3: Effects of Arhgap26 deletion on the quality of mouse ovulated oocytes.
Fig. 4: Effects of heterozygous deletion of Arhgap26 on the quality of mouse GV and ovulated oocytes.
Fig. 5: Effects of Arhgap26 deletion on the transcriptome profiling of mouse GV oocytes.
Fig. 6: Effects of Arhgap26 deletion on the dynamics of Cofilin1 and Drp1 in mouse oocytes.
Fig. 7: Expression of exogenous Arhgap26 restores the quality of Arhgap26-null oocytes.
Fig. 8: Chromosomal microarray analysis of peripheral blood from a patient with recurrent miscarriage.

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All study data are included in the article and Supplementary information. Data supporting the findings of this study are available on reasonable request from the corresponding authors.

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Funding

This work was supported by the National Key Research and Development Program of China (2021YFC2700100) and the National Natural Science Foundation of China (32070836).

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Author notes

  1. These authors contributed equally: Sen Li, Yu Zhang.

Authors and Affiliations

  1. Fertility Preservation Lab, Reproductive Medicine Center, Guangdong Second Provincial General Hospital, Guangzhou, China

    Sen Li, Ruiying Yuan & Xianghong Ou

  2. College of Animal Sciences, Zhejiang University, Hangzhou, China

    Yu Zhang & Bo Xiong

  3. College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China

    Yu Zhang, Jie Bai, Yilong Miao & Bo Xiong

  4. State Key Laboratory of Reproductive Medicine and Offspring Health, Changzhou Maternity and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, Nanjing, China

    Shuai Zhu & Qiang Wang

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  1. Sen Li
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Contributions

BX and XO conceived and designed the research; SL, YZ, RY, SZ, JB and YM performed the experiments; SL, YZ, XO, QW and BX analyzed the data; SL, XO, QW and BX wrote the manuscript.

Corresponding authors

Correspondence to Xianghong Ou, Qiang Wang or Bo Xiong.

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Competing interests

The authors declare no competing interests.

Ethics approval

This study was approved by the Institutional Review Board (IRB) of Guangdong Second Provincial General Hospital (2018-SZYX-013), China. The peripheral blood sample was donated by the patient after signing the informed consent at the Center for Reproductive Medicine in Guangdong Second Provincial General Hospital. The patient was informed that her peripheral blood would be used for chromosomal microarray. All mouse experiments were performed in accordance with the Animal Research Institute Committee guidelines of Nanjing Agricultural University, China.

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Li, S., Zhang, Y., Yuan, R. et al. ARHGAP26 deficiency drives the oocyte aneuploidy and early embryonic development failure. Cell Death Differ (2024). https://doi.org/10.1038/s41418-024-01384-5

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