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 extreme 1,2 . Despite decades of effort, spermiogenesis remains difficult to recapitulate outside the testis 2,3 , 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 Ca 2+ 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 organs 4,5 . Mechanistically, loss of Tmc5 blocks mechanically evoked Ca 2+ entry, leading to disruptions in cytoskeletal remodeling and failure of CREMτ-dependent transcriptional programs required for spermiogenesis 6 . Thus, TMC5 is required to couple mechanical cues to sperm development, with direct implications for male infertility.