ARHGEF15, also known as EPHEXIN5, is a guanine nucleotide-exchange factor (GEF) that activates the Rho protein. It is involved in multiple biological processes such as cell migration, cell polarity, and cell cycle progression via Rho GTPases activation. It participates in pathways like the Wnt/β -catenin signaling pathway in osteoblast cells and is associated with the regulation of the F -actin cytoskeleton in vascular smooth muscle and endothelial cells [1].

In gene-targeted mouse models, Arhgef15 knockout and conditional knockout (CKO) mice have provided valuable insights. SC-specific Arhgef15 knockout mice showed disrupted blood-testis barrier integrity, abnormal sperm development, and impaired testicular immune privilege [2]. Arhgef15-e(V368M)1 transgenic mice developed cerebral small vessel disease (CSVD)-like pathological and behavioral phenotypes along with severe osteoporosis. In vitro experiments indicated that ARHGEF15 mutations led to RhoA/ROCK2 inactivation-induced F -actin cytoskeleton disorganization in relevant cells and osteoblast dysfunction through inhibiting the Wnt/β -catenin signaling pathway [1].

In conclusion, ARHGEF15 plays essential roles in spermatogenesis-related processes such as germ cell development and testicular immune privilege, as well as in conditions like CSVD and osteoporosis. The use of Arhgef15 KO and CKO mouse models has significantly enhanced our understanding of these disease-associated functions, providing potential insights for therapeutic strategies in related diseases [1,2].