Abstract
Mammalian fertilization is a complex process involving a series of successive sperm-egg interaction steps mediated by different molecules and mechanisms. Studies carried out during the past 30 years, using a group of proteins named CRISP (Cysteine-RIch Secretory Proteins), have significantly contributed to elucidating the molecular mechanisms underlying mammalian gamete interaction. The CRISP family is composed of four members (i.e., CRISP1-4) in mammals, mainly expressed in the male tract, present in spermatozoa and exhibiting Ca2+ channel regulatory abilities. Biochemical, molecular and genetic approaches show that each CRISP protein participates in more than one stage of gamete interaction (i.e., cumulus penetration, sperm-ZP binding, ZP penetration, gamete fusion) by either ligand-receptor interactions or the regulation of several capacitation-associated events (i.e., protein tyrosine phosphorylation, acrosome reaction, hyperactivation, etc.) likely through their ability to regulate different sperm ion channels. Moreover, deletion of different numbers and combination of Crisp genes leading to the generation of single, double, triple and quadruple knockout mice showed that CRISP proteins are essential for male fertility and are involved not only in gamete interaction but also in previous and subsequent steps such as sperm transport within the female tract and early embryo development. Collectively, these observations reveal that CRISP have evolved to perform redundant as well as specialized functions and are organized in functional modules within the family that work through independent pathways and contribute distinctly to fertility success. Redundancy and compensation mechanisms within protein families are particularly important for spermatozoa which are transcriptionally and translationally inactive cells carrying numerous protein families, emphasizing the importance of generating multiple knockout models to unmask the true functional relevance of family proteins. Considering the high sequence and functional homology between rodent and human CRISP proteins, these observations will contribute to a better understanding and diagnosis of human infertility as well as the development of new contraceptive options.
Highlights
In mammals, sperm that leave the testes are not capable of recognizing and fertilizing the egg
Oviductal migration defects for Crisp1−/−/Crisp3−/−cannot be excluded, the normal in vivo fertilization rates observed for this colony does not favor this possibility. These observations support that oviductal migration defects in multiple knockout mice are likely due to the midpiece rigidity phenotype observed in ejaculated Triple knockout (TKO) and quadruple knockout (QKO) (Lim et al, 2019; Curci et al, 2020) but not in Crisp1−/−/Crisp3−/− sperm, associated with the lack of Crisp2 and leading to defects in hyperactivation known to be required for detaching sperm from the isthmus epithelium
Biochemical, cellular and genetic approaches revealed that Cysteine-RIch Secretory Protein (CRISP) proteins play key functional roles in the successive stages of the fertilization process through different mechanisms that include ligand-receptor interactions as well as regulation of several capacitation-associated events, likely through their ability to regulate different Ca2+ channels
Summary
Sperm that leave the testes are not capable of recognizing and fertilizing the egg. Patch-clamp of murine testicular sperm revealed that the CRD domain of CRISP4 has the ability to inhibit TRPM8 without affecting capacitation-associated parameters (i.e., sperm tyrosine phosphorylation or progesterone-induced acrosome reaction) (Gibbs et al, 2011) These observations together with the lack of a loosely bound population support a role for CRISP4 in gamete interaction rather than as a decapacitating factor as previously proposed for CRISP1. The reported observations indicate that CRISP proteins exhibit a high sequence, structural and functional homology being involved in different stages of the fertilization process To better analyze their functional roles as well as their relevance for fertility, our laboratory and others have generated several knockout models for CRISP family members (i.e., single, double and multiple knockouts) which exhibit different phenotypes described in detail
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