Loss of α-catenin in germ cells impairs spermatogenesis and flagellar function associated with teratozoospermia

Infertility affects approximately 10%-20% of couples worldwide, with male factors accounting for roughly half of all cases. Teratozoospermia, defined by the occurrence of abnormally shaped sperm, is a significant contributor to male infertility. Here, by analyzing a publicly available RNA array dataset comparing teratozoospermia patients and normal controls, we uncovered disrupted adherens junction (AJ)-associated signaling and defective spermatogenesis within germ cells of teratozoospermia patients. In AJs, α-catenin (CTNNA1) anchors the cadherin-catenin complex to the actin cytoskeleton and regulates actin organization, but its role in germ cell development and sperm function remains unknown. We generated a germ cell-specific Ctnna1 conditional knockout mouse model (Ctnna1cKO). Homozygous Ctnna1-deficient mice exhibited male infertility with abnormal structure and function of spermatozoa. Single-cell RNA sequencing of control and Ctnna1cKO testes revealed an accumulation of spermatogonia with impaired differentiation and abnormal acrosome structure in Ctnna1-deficient mice, likely caused by disrupted splicing and meiotic processes through dysregulated vinculin. Additionally, loss of α-catenin disrupted both direct and indirect interactions between spermatogenic cells and Sertoli cells, as evidenced by N-cadherin internalization that mediates their adhesion and by reduced Cyclophilin A/CD147 paracrine signaling essential for spermatogenesis. Mechanistically, loss of α-catenin results in disorganization of the α-catenin/vinculin/N-cadherin complex, leading to defective cell-cell interactions and impairment of spermatogenesis. Collectively, our study establishes α-catenin as a critical regulator of spermatogenesis and germ cell development and highlights its potential as a prognostic biomarker and therapeutic target for male infertility, particularly teratozoospermia.