Cysteine-Rich Secretory Proteins in Reproductive Biology

Cysteine-Rich Secretory Proteins (CRISPs) constitute a conserved family of small, secreted proteins characterised by an N-terminal PR-1 domain and a distinctive cysteine-rich C-terminal region. Predominantly expressed in the male reproductive tract, CRISPs associate with sperm during epididymal maturation and mediate multiple stages of fertilisation, including cumulus penetration, zona pellucida binding and gamete fusion. Their high content of disulfide bonds confers structural stability and enables interactions with ion channels, notably ryanodine receptors and other Ca2+-permeable channels, modulating capacitation-associated signalling, acrosome exocytosis and hyperactivated motility. Genetic ablation studies in rodents have revealed both redundant and specialised functions within the CRISP family, underscoring their evolutionary divergence and compensation mechanisms. Beyond basic fertilisation, CRISPs contribute to the maintenance of epididymal epithelium integrity and immunotolerance in the female tract. Owing to their conserved sequences across mammals and localisation in seminal plasma, CRISPs are under investigation as biomarkers for male fertility and as potential targets for non-hormonal contraception.

Research from Nature Portfolio

Work using double knockout mice lacking both CRISP1 and CRISP4 has demonstrated that simultaneous loss of these epididymal proteins leads to pronounced fertility defects. While single-gene deletions had minimal impact, the double mutants exhibited impaired sperm–egg fusion and, in a subset of animals, pronounced epididymo-orchitis with disrupted epithelial differentiation and altered luminal pH. These findings reveal that CRISP1 and CRISP4 are not only essential for the fine-tuning of sperm fertilising ability but also play a key role in the maturation and immune environment of the male tract, highlighting interdependence between reproductive and epithelial cell biology.

Cysteine-Rich Secretory Proteins in Reproductive Biology publication trend

The graph below shows the total number of articles in cysteine-rich secretory proteins in reproductive biology across all publications each year (not limited to Nature Index journals).

Technical terms

Cysteine-Rich Secretory Protein (CRISP): A family of small, secreted proteins rich in disulfide bonds, involved in sperm maturation and fertilisation.

Capacitation: A physiological maturation process in the female tract that renders spermatozoa capable of fertilising an oocyte.

Acrosome Reaction: Exocytosis of the acrosomal vesicle at the sperm head, enabling penetration of the zona pellucida.

Hyperactivation: A change to a high-amplitude, asymmetric flagellar beat necessary for zona penetration.

Epididymis: A duct behind the testis where sperm mature and acquire motility.

Zona Pellucida: The glycoprotein envelope surrounding the oocyte that must be traversed for fertilisation.

References

1. Semen Protein CRISP3 Promotes Reproductive Performance of Boars through Immunomodulation. International Journal of Molecular Sciences (2024).
2. The Cysteine-rich Secretory Protein Domain of Tpx-1 Is Related to Ion Channel Toxins and Regulates Ryanodine Receptor Ca2+ Signaling*. Journal of Biological Chemistry (2005).
3. Impaired male fertility and abnormal epididymal epithelium differentiation in mice lacking CRISP1 and CRISP4. Scientific Reports (2018).
4. Cysteine-Rich Secretory Proteins (CRISP) are Key Players in Mammalian Fertilization and Fertility. Frontiers in Cell and Developmental Biology (2021).
5. Evolutionary analysis of genes coding for Cysteine-RIch Secretory Proteins (CRISPs) in mammals. BMC Ecology and Evolution (2020).
6. CRISPs Function to Boost Sperm Power Output and Motility. Frontiers in Cell and Developmental Biology (2021).