Loss of TMC7 causes male infertility with disrupted spermiogenesis in mice.
TL;DR
Findings demonstrate that transmembrane channel-like protein 7 plays a critical role in spermiogenesis and indirectly contributes to the maintenance of ICB integrity.
Abstract
Spermatogenesis is a highly ordered developmental process that occurs in the seminiferous tubules and involves mitotic proliferation of spermatogonial stem cells, meiotic division of spermatocytes, and post-meiotic spermiogenesis, ultimately producing mature spermatozoa. Defects at any stage of this process can lead to male infertility. Large-scale transcriptomic and proteomic studies have identified thousands of testis-enriched genes in humans and mice, supporting the use of mouse models to uncover genetic regulators of male fertility. In this study, we focused on transmembrane channel-like protein 7 (TMC7), which is highly expressed in the testis. To investigate its physiological function, we generated a Tmc7 knockout (KO) mouse line using the CRISPR/Cas9 system. Tmc7 KO male mice were sterile, and no spermatozoa were observed in the epididymis. Instead, multinucleated giant cells containing multiple elongating spermatids were detected in the lumens of seminiferous tubules. We found that these abnormalities were associated with defective intercellular bridge (ICB) stabilization. Transmission electron microscopy further revealed that spermatid nuclei passed through gaps within the ICBs, leading to the formation of multinucleated giant cells. Given the Golgi localization of TMC7, ICB destabilization may occur secondarily due to blood-testis barrier disruption caused by alterations in the testicular microenvironment. Importantly, ectopic expression of TMC7 in Tmc7 KO mice rescued the defective spermiogenesis phenotype. Taken together, these findings demonstrate that TMC7 plays a critical role in spermiogenesis and indirectly contributes to the maintenance of ICB integrity.