News Release

Tissue proteolysis and male infertility

Peer-Reviewed Publication

JCI Journals

Here, Uhrin et al. describe the targeted disruption of the PCI gene, which encodes the protein C inhibitor. This member of the serpin family of proteinase inhibitors was originally known for its role in regulating thrombosis, but its biochemical specificity is broad, as is its distribution in human extravascular tissues. PCI–/– mice are indistinguishable from their wild-type littermates in most respects, but males are infertile, due to profound defects in sperm development. Remarkably, human male infertility is also associated with a lack of PCI in the seminal fluid — normally a rich source of this proteinase inhibitor in both humans and mice. Uhrin and coworkers propose that the absence of PCI perturbs the balance of endogenous proteinases and proteinase inhibitors in the male reproductive tract. As measured in vitro using artificial substrates, the activity of multiple serine proteinases in the testis is greatly increased in the mutant males. Presumably as a consequence of this unbalanced proteolytic activity, the histological structure of the seminiferous tubules is disrupted, with considerable cell death among Sertoli cells and spematogenic precursor cells. Sperm cells themselves are abnormal and are incapable of binding oocytes, even from wild-type females. Because of the multiple defects in the testis that could account for the abnormalities in the sperm, the present findings do not address whether the loss of PCI directly affects sperm-associated proteinases, such as the serine proteinase acrosin.

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