Disruption of the protein C inhibitor gene results in impaired spermatogenesis and male infertility

Protein C inhibitor (PCI) is a nonspecific, heparin-binding serpin (serine protease inhibitor) that inactivates many plasmatic and extravascular serin e proteases by forming stable 1:1 complexes. Proteases inhibited by PCI inc lude the anticoagulant activated protein C, the plasminogen activator uroki nase, and the sperm protease acrosin, In humans PCI circulates as a plasma protein but is also present at high concentrations in organs of the male re productive tract. The biological role of PCI has not been defined so far. H owever, the colocalization of high concentrations of PCI together with seve ral of its target proteases in the male reproductive tract suggests a role of PCI in reproduction. We generated mice lacking PCI by homologous recombi nation. Here rye show that PCI-/- mice are apparently heal thy but that mal es of this genotype are infertile, Infertility was apparently caused by abn ormal spermatogenesis due to destruction of the Sertoli cell barrier, perha ps due to unopposed proteolytic activity. The resulting sperm are malformed and are morphologically similar to abnormal sperm seen in some cases of hu man male infertility. This animal model might therefore be useful for analy zing the molecular bases of these human conditions.