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WORLD OF REPRODUCTIVE BIOLOGY

The b-defensins, best known as antimicrobial peptides, are necessary for proper sperm maturation, according to a new study in mice. The peptides seem to prevent the sperm from undergoing premature capacitation, a process that normally occurs in the female reproductive tract. Mice and humans each have dozens of b-defensin genes, which are thought to play a major role in innate immune defense and fighting off various microbes. The b-defensins have also been implicated in male reproduction. In rats, for instance, some b-defensins influence sperm motility, and in humans, the b-defensin DEFB126 seems to influence the ability of sperm to penetrate female cervical secretions; men with homozygous mutations in this gene have impaired fertility. To examine the function of b-defensins more closely, Yu S. Zhou et al. deleted nine b-defensin genes in a gene cluster on a single chromosome that were expressed most strongly in the male reproductive tract in mice. Four of these genes have human orthologs that are also expressed strongly in the male reproductive tract. The researchers found that male mice lacking all nine genes were infertile. Their sperm were fragile, with the heads easily breaking off from the tails. Closer analysis revealed that the sperm had elevated levels of calcium and increased spontaneous acrosome reactions (as indicated by changes in the composition of membrane proteins and other molecular markers), all of which suggested that the sperm underwent premature capacitation in the male reproductive tract. Capacitation involves changes in membrane properties and an increase in intracellular calcium; the result is an increase in motility and an induction of the acrosome reaction, which are necessary steps for sperm to fuse with the oocyte. If these changes occur prematurely, however, the induced destabilization of microtubules leads to poor sperm motility and ultimately to infertility (Fig. 1). The researchers speculate that b-defensins may control the entry of calcium into calcium channels. Future studies could explore the potential value of these peptides as targets for contraceptive development, perhaps for use as topical contraceptives in the female reproductive tract.