Relevance of CRISP proteins for epididymal physiology, fertilization and fertility

CUASNICÚ PS; BATTISTONE MA; CARVAJAL G; BRETON S; WEIGEL MUÑOZ M; LUSTIG L; BRUKMAN NG

Conferencia; Gordon Research Conference, Fertilization & Activation of Development.; 2017

Epididymal proteins CRISP1 and CRISP4 associate with sperm during maturation and  participate in different stages of the fertilization process. Whereas both CRISP1 and CRISP4 have the ability to regulate TRPM8 calcium channels, recent evidence revealed that CRISP1 is also capable of regulating CatSper, the principal sperm Ca2+ channel involved in hyperactivation and essential for male fertility. In spite of their critical roles for fertilization, the knockout (KO) mice for each of these molecules are fertile, suggesting compensatory mechanisms between the two proteins. To address this question, we generated CRISP1/CRISP4 double KO (DKO) mice and examined their phenotype. DKO males exhibited severe defects in fertility (p*<0.001) which correlated with significantly p*<0.001) lower in vivo fertilization rates. Further examination of the DKO animals revealed that one third of the males exhibited clear signs of inflammation in the epididymis as judged by the finding that both the caput and corpus regions were bigger than controls, had a severely damaged epithelium, presence of immune cells in the lumen and interstitium and significantly lower levels of sperm viability. Interestingly, however, the 2/3 of males with no signs of inflammation and normal sperm viability also showed significantly (p*<0.05) lower fertility than controls, supporting the involvement of CRISP proteins in fertilization as responsible for their fertility defects. Together, these results provide the first evidence on the relevance of CRISP proteins not only for fertilization but also for animal fertility, confirmed the existence of compensatory mechanisms between homologous CRISP proteins, and revealed novel immunoregulatory roles for these proteins in epididymal physiology.