Cellular morphogenesis relies on the dynamic remodeling of membranes in response to mechanical and osmotic forces. In the testis, developing germ cells must adapt to osmotic fluctuations and mechanical stresses during differentiation. This process is most striking in spermiogenesis, when haploid round spermatids undergo nuclear shaping, cytoplasmic reduction, and elongation to become highly polarized. Despite the magnitude of these structural transformations, the underlying membrane-based mechanisms remain poorly understood. We identify TMC5, a previously uncharacterized member of the transmembrane channel-like (TMC) family, as an essential regulator of spermatid morphogenesis. We find, using TMC5-mCherry knockin mice that TMC5 localizes to the plasma membrane of round and elongated spermatids. Loss of Tmc5 in mice leads to male infertility due to arrest of spermiogenesis. TMC5 shares significant sequence and structural homology with TMC1, which interacts with calcium and integrin binding protein (CIB) to form a cation-selective mechanosensitive ion channel in sensory cells of the inner ear. We thus hypothesized that a similar TMC5-CIB may also couple ionic conductance to membrane remodeling during sperm development. In support of this, we find that TMC5 in spermatids also interacts with CIB proteins, and that CIB1 requires TMC5 for correct membrane localization. Functionally, preliminary calcium imaging data revealed that wild-type spermatids respond to osmotically driven changes in membrane tension with robust calcium influx, a response that is diminished in TMC5 knockout spermatids. Together, these findings establish TMC5 as a mechanosensory hub that links ionic and lipid dynamics to regulate spermatid morphogenesis. More broadly, they point to the existence of conserved TMC-CIB mechanosensitive complexes that link membrane mechanics to cellular function across diverse tissues.
Zheng et al. (Sun,) studied this question.