Gonzalez Soledad N, Sulzyk Valeria, Weigel Muñoz Mariana, Cuasnicu Patricia S
Instituto de Biología y Medicina Experimental (IByME-CONICET), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina.
Front Cell Dev Biol. 2021 Dec 14;9:800351. doi: 10.3389/fcell.2021.800351. eCollection 2021.
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 Ca 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 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.
哺乳动物受精是一个复杂的过程，涉及一系列由不同分子和机制介导的连续的精卵相互作用步骤。在过去30年中，对一组名为CRISP（富含半胱氨酸的分泌蛋白）的蛋白质进行的研究，为阐明哺乳动物配子相互作用的分子机制做出了重大贡献。CRISP家族在哺乳动物中由四个成员（即CRISP1 - 4）组成，主要在雄性生殖道中表达，存在于精子中，并具有钙通道调节能力。生化、分子和遗传学方法表明，每种CRISP蛋白通过配体 - 受体相互作用或调节几种获能相关事件（即蛋白质酪氨酸磷酸化、顶体反应、超活化等），可能通过其调节不同精子离子通道的能力，参与配子相互作用的多个阶段（即卵丘穿透、精子 - 透明带结合、透明带穿透、配子融合）。此外，通过删除不同数量和组合的基因来产生单基因、双基因、三基因和四基因敲除小鼠，结果表明CRISP蛋白对雄性生育能力至关重要，不仅参与配子相互作用，还参与之前和之后的步骤，如雌性生殖道内的精子运输和早期胚胎发育。总体而言，这些观察结果表明，CRISP已经进化到执行冗余以及专门的功能，并在家族内组织成功能模块，这些模块通过独立的途径发挥作用，并对生育成功有明显贡献。蛋白质家族内的冗余和补偿机制对于精子尤为重要，精子是转录和翻译不活跃的细胞，携带众多蛋白质家族，这强调了生成多个敲除模型以揭示家族蛋白真正功能相关性的重要性。考虑到啮齿动物和人类CRISP蛋白之间的高度序列和功能同源性，这些观察结果将有助于更好地理解和诊断人类不孕症以及开发新的避孕方法。
