CRISP2 is a regulator of multiple aspects of sperm function and male fertility.

The Cysteine-RIch Secretory Proteins (CRISPs) are a group of proteins which show a pronounced expression biased to the male reproductive tract. While sperm encounter CRISPs at virtually all phases of sperm development and maturation, CRISP2 is the sole CRISP produced during spermatogenesis, wherein it is incorporated into the developing sperm head and tail. Within this study we test the necessity for CRISP2 in male fertility using Crisp2 loss-of-function mouse models. In doing so, we reveal a role for CRISP2 in establishing the ability of sperm to undergo the acrosome reaction, and in establishing a normal flagellum wave form. Crisp2 deficient sperm possess a stiff mid-piece and are thus unable to manifest the rapid form of progressive motility seen in wild type sperm. As a consequence, Crisp2 deficient males are sub-fertile. Further, a yeast-two hybrid screen and immunoprecipitation studies reveal that CRISP2 can bind to the CATSPER1 subunit of the Catsper ion channel which is required for normal sperm motility. Collectively, these data define CRISP2 as a determinant of male fertility and explain previous clinical associations between human CRISP2 expression and fertility.