Howard Hughes Medical Institute, Boston Children's Hospital, Boston, United States; Department of Neurobiology, Harvard Medical School, Boston, United States; Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, United States
Kiyoshi Miki
Howard Hughes Medical Institute, Boston Children's Hospital, Boston, United States
Doory Kim
Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States; Department of Physics, Harvard University, Cambridge, United States
Sang-Hee Shim
Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States; Department of Physics, Harvard University, Cambridge, United States
Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States; Department of Physics, Harvard University, Cambridge, United States
Howard Hughes Medical Institute, Boston Children's Hospital, Boston, United States; Department of Neurobiology, Harvard Medical School, Boston, United States
We report that the Gm7068 (CatSpere) and Tex40 (CatSperz) genes encode novel subunits of a 9-subunit CatSper ion channel complex. Targeted disruption of CatSperz reduces CatSper current and sperm rheotactic efficiency in mice, resulting in severe male subfertility. Normally distributed in linear quadrilateral nanodomains along the flagellum, the complex lacking CatSperζ is disrupted at ~0.8 μm intervals along the flagellum. This disruption renders the proximal flagellum inflexible and alters the 3D flagellar envelope, thus preventing sperm from reorienting against fluid flow in vitro and efficiently migrating in vivo. Ejaculated CatSperz-null sperm cells retrieved from the mated female uterus partially rescue in vitro fertilization (IVF) that failed with epididymal spermatozoa alone. Human CatSperε is quadrilaterally arranged along the flagella, similar to the CatSper complex in mouse sperm. We speculate that the newly identified CatSperζ subunit is a late evolutionary adaptation to maximize fertilization inside the mammalian female reproductive tract.
