Abstract
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.
Highlights
Sperm hyperactivation, characterized by a large asymmetric lateral displacement of the flagellum (Ishijima et al, 2002), is required for normal mammalian sperm navigation (Demott and Suarez, 1992), rheotaxis (Miki and Clapham, 2013), and zona pellucida (ZP) penetration (Stauss et al, 1995)
As the most biochemically complex ion channel known to date, it has not been possible to express functional CatSper channels in heterologous systems
A small soluble protein encoded by another testis-specific gene, Tex40 (Figure 1—figure supplement 2A), was found to be associated with the CatSper channel complex (Figure 1B and C, and Figure 1—figure supplement 1D)
Summary
Sperm hyperactivation, characterized by a large asymmetric lateral displacement of the flagellum (Ishijima et al, 2002), is required for normal mammalian sperm navigation (Demott and Suarez, 1992), rheotaxis (Miki and Clapham, 2013), and zona pellucida (ZP) penetration (Stauss et al, 1995). Calcium influx through the flagellar Ca2+ ion channel, CatSper, triggers hyperactivation (Carlson et al, 2003; Kirichok et al, 2006; Ren et al, 2001) and leads to changes in the flagellar envelope during capacitation (Chung et al, 2011; Quill et al, 2003).
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