Sperm development requires TMC5-dependent mechanoresponsive calcium entry

Abstract

Spermiogenesis, the transformation of round spermatids into streamlined, fertilization-competent sperm, represents cellular morphogenesis at its most extreme1,2. Despite decades of effort, spermiogenesis remains difficult to recapitulate outside the testis2,3, highlighting the importance of cues within the native tissue environment. The nature of these cues, however, remains poorly understood. Here, we discover that mechanical stimulation elicits Ca2+ entry in spermatids and identify transmembrane channel-like protein 5 (TMC5) as a principal mediator of this response. In both mouse and human testes, TMC5 is selectively expressed in spermatids and localized to the plasma membrane. TMC5 associates with TMC7 and calcium- and integrin-binding (CIB) proteins, mirroring TMC–CIB mechanotransduction complexes in sensory organs4,5. Mechanistically, loss of Tmc5 blocks mechanically evoked Ca2+ entry, leading to disruptions in cytoskeletal remodeling and failure of CREMτ-dependent transcriptional programs required for spermiogenesis6. Thus, TMC5 is required to couple mechanical cues to sperm development, with direct implications for male infertility.