RhoGDI alpha regulates spermatogenesis through Rac1/cofilin/F-actin signaling

Spermatogenesis is an extremely complex process, and any obstruction can cause male infertility. RhoGDI alpha has been identified as a risk of male sterility. In this study, we generate RhoGDI alpha knockout mice, and find that the males have severely low fertility. The testes from RhoGDI alpha(-/-) mice are smaller than that in WT mice. The numbers of spermatogonia and spermatocytes are decreased in RhoGDI alpha(-/-) testis. Spermatogenesis is compromised, and spermatocyte meiosis is arrested at zygotene stage in RhoGDI alpha(-/-) mice. Acrosome dysplasia is also observed in sperms of the mutant mice. At the molecular level, RhoGDI alpha deficiency activate the LIMK/cofilin signaling pathway, inhibiting F-actin depolymerization, impairing testis and inducing low fertility in mouse. In addition, the treatment of RhoGDI alpha(-/-) mice with Rac1 inhibitor NSC23766 alleviate testis injury and improve sperm quality by inhibiting the LIMK/cofilin/F-actin pathway during spermatogenesis. Together, these findings reveal a previously unrecognized RhoGDI alpha/Rac1/F-actin-dependent mechanism involved in spermatogenesis and male fertility. RhoGDI alpha knockout mice show low male fertility and compromised spermatogenesis, with an underlying defect in F-actin cytoskeleton depolymerisation, which can be alleviated by inhibiting Rac1.