E2F1 regulates testicular descent and controls spermatogenesis by influencing WNT4 signaling.

Cryptorchidism is the most common urologic birth defect in men and is a predisposing factor of male infertility and testicular cancer, yet the etiology remains largely unknown. microdeletions and microduplications contribute to cryptorchidism, infertility and testicular tumors. Although deletion or overexpression in mice causes spermatogenic failure, the mechanism by which influences testicular function is unknown. This investigation revealed that null mice develop cryptorchidism with severe gubernacular defects and progressive loss of germ cells resulting in infertility and, in rare cases, testicular tumors. It was hypothesized that germ cell depletion resulted from an increase in WNT4 levels. To test this hypothesis, the phenotype of a double-null mouse model lacking both and in germ cells was analyzed. Double-null mice are fertile. This finding indicates that germ cell maintenance is dependent on repression of , supporting a role for in germ cell survival. In the future, modulation of expression in men with cryptorchidism and spermatogenic failure due to copy number variations may provide a novel approach to improve their spermatogenesis and perhaps their fertility potential after orchidopexy.