Cysteine-Rich Secretory Proteins (CRISP) are Key Players in Mammalian Fertilization and Fertility

GONZALEZ, SN; SULZYK, VALERIA; WEIGEL MUÑOZ, M; CUASNICU P S

Frontiers in Cell and Developmental Biology

Frontiers Media S.A.

Año: 2021

2296-634X

Mammalian fertilization is a complex process involving a series of successive sperm-egginteraction steps mediated by different molecules and mechanisms. Studies carried outduring the past 30 years, using a group of proteins named CRISP (Cysteine-RIchSecretory Proteins), have significantly contributed to elucidating the molecularmechanisms underlying mammalian gamete interaction. The CRISP family iscomposed of four members (i.e., CRISP1-4) in mammals, mainly expressed in themale tract, present in spermatozoa and exhibiting Ca2+ channel regulatory abilities.Biochemical, molecular and genetic approaches show that each CRISP proteinparticipates in more than one stage of gamete interaction (i.e., cumulus penetration,ZP-binding, ZP penetration, gamete fusion) by either ligand-receptor interactions or theregulation of several capacitation-associated events (i.e., protein tyrosine phosphorylation,acrosome reaction, hyperactivation, etc.) likely through their ability to regulate differentsperm ion channels. Moreover, deletion of different numbers and combination of Crispgenes leading to the generation of single, double, triple and quadruple knockout miceshowed that CRISP proteins are essential for male fertility and are involved not only ingamete interaction but also in previous and subsequent steps such as sperm transportwithin the female tract and early embryo development. Collectively, these observationsreveal that CRISP have evolved to perform redundant as well as specialized functions andare organized in functional modules within the family that work through independentpathways and contribute distinctly to fertility success. Redundancy and compensationmechanisms within protein families are particularly important for spermatozoa which aretranscriptionally and translationally inactive cells carrying numerous protein families,emphasizing the importance of generating multiple knockout models to unmask thetrue functional relevance of family proteins. Considering the high sequence andfunctional homology between rodent and human CRISP proteins, these observationswill contribute to a better understanding and diagnosis of human infertility as well as thedevelopment of new contraceptive options.