ARHGAP26 deficiency drives the oocyte aneuploidy and early embryonic development failure.

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.