Abstract
Epididymal Cysteine Rich Secretory Proteins 1 and 4 (CRISP1 and CRISP4) associate with sperm during maturation and play different roles in fertilization. However, males lacking each of these molecules individually are fertile, suggesting compensatory mechanisms between these homologous proteins. Based on this, in the present work, we generated double CRISP1/CRISP4 knockout (DKO) mice and examined their reproductive phenotype. Our data showed that the simultaneous lack of the two epididymal proteins results in clear fertility defects. Interestingly, whereas most of the animals exhibited specific sperm fertilizing ability defects supportive of the role of CRISP proteins in fertilization, one third of the males showed an unexpected epididymo-orchitis phenotype with altered levels of inflammatory molecules and non-viable sperm in the epididymis. Further analysis showed that DKO mice exhibited an immature epididymal epithelium and abnormal luminal pH, supporting these defects as likely responsible for the different phenotypes observed. These observations reveal that CRISP proteins are relevant for epididymal epithelium differentiation and male fertility, contributing to a better understanding of the fine-tuning mechanisms underlying sperm maturation and immunotolerance in the epididymis with clear implications for human epididymal physiology and pathology.
Highlights
Gamete interaction in mammals involves a series of sequential and coordinated steps that culminates in the union of the sperm and egg genomes
In the present work, we analyzed the reproductive phenotype of mice lacking both CRISP1 and CRISP4 revealing the relevance of these proteins for male fertility as well as for proper epididymal epithelium differentiation and luminal acidification
CRISP1 and CRISP4 are expressed in high concentrations in the epididymis where they associate with sperm plasma membrane
Summary
Gamete interaction in mammals involves a series of sequential and coordinated steps that culminates in the union of the sperm and egg genomes. The mechanisms underlying the acquisition of sperm fertilizing ability are still under investigation[4,5], it is known that sperm maturation involves numerous changes at the gamete surface level, most of which occur as a result of the association of epididymal proteins with the sperm plasma membrane[6,7]. Two such proteins are CRISP1 and CRISP48–11 which belong to a highly conserved and widely distributed family among vertebrates known as Cysteine RIch Secretory Proteins (CRISP). In the present work, we analyzed the reproductive phenotype of mice lacking both CRISP1 and CRISP4 revealing the relevance of these proteins for male fertility as well as for proper epididymal epithelium differentiation and luminal acidification
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