Male reproductive phenotypes in double mutant mice lacking both FSHbeta and activin receptor IIA

Activins are known to signal through two serine/threonine kinase type II receptors. Activin receptor IIA is widely expressed in the male reproductive axis, including the pituitary and testis. Our previous studies using gene knockout mice have confirmed the essential in vivo role of activin receptor IIA in FSH homeostasis. Activin receptor IIA-null male mice are fertile, have suppressed pituitary and serum FSH levels, and demonstrate a decrease in testis size as a result of reduced Sertoli cells and germ cells. Similarly, FSHbeta null male mice are fertile despite reduced testis size and Sertoli cell number. To define the direct roles of activin receptor IIA signaling locally in the testis, independent of its effects on FSH homeostasis, we generated double mutant mice lacking both activin receptor IIA and FSH by a genetic intercross and analyzed the male reproductive phenotypes. The double mutant male mice lacking both FSH and activin receptor IIA are fertile, demonstrate no significant reduction in testis size, and produce small litters compared with mice lacking either FSH or activin receptor IIA alone. Histological analyses of the testes from double mutant mice revealed the presence of normal stages of spermatogenesis. However, there was a significant reduction in the epididymal sperm number compared with that of the individual mutants. Northern blot analyses of total RNA from testes of double mutants did not reveal transcriptional up-regulation of activin receptor IIB, the other activin type II receptor. Although RNA expression profiles of many testis cell-specific markers are unaltered, stereological analysis of the testes from double mutants indicates that there was a reduction in type A and I spermatogonial number compared with that observed in individual mutants. Our results provide in vivo genetic evidence to demonstrate that activin receptor IIA signaling plays an important local role within the testis, independent of its actions via FSH homeostasis in the pituitary.