Disruption of TEX38 impairs sperm morphogenesis and the migration of sperm into the oviduct

In male reproduction, spermatogenesis and sperm maturation are critical for the production of normal sperm and offspring, yet the underlying molecular mechanisms remain largely elusive. Tex38 is a testis-enriched gene, and its deficiency results in oligoasthenoteratospermia (OAT) with aberrant epididymis, leading to male infertility in mice. Tex38 knockout (KO) sperm primarily exhibited neck bending deformities and functional abnormalities, including impaired fertilization. Proteomic analysis identified ADAM3 and its maturation-associated chaperones (CALR3, CLGN, and PDILT) as the most significantly altered proteins among the differentially expressed proteins (DEPs) in both sperm and epididymis of Tex38 knockout mice. GO analysis revealed that DEPs were primarily involved in sperm morphogenesis, motility, and fertilization. ARRDC5 was identified as a novel interacting protein of TEX38, and its deletion resulted in similar male infertility phenotypes as Tex38 deletion. Immunoprecipitation-mass spectrometry identified TEX38 and ARRDC5 interact with CLGN and PDILT. The interactions among TEX38, ARRDC5, PDILT, and CLGN were found to affect ADAM3 maturation, resulting in the failure of both Tex38^-/- and Arrdc5^-/- sperm to migrate to the oviduct. Overall, these findings establish TEX38 as an essential regulator of mammalian ADAM3-related migration, sperm formation, energy metabolism (ATP generation), sperm-egg binding and fertilization. TEX38 represents a potential target for diagnosis and treatment of male infertility and male contraception.