Testis-derived testosterone has been recognized as the key factor for morphogenesis of the Wolffian duct, the precursor of several male reproductive tract structures. Evidence supports that testosterone is required for the maintenance of the Wolffian duct via its action on the mesenchyme. However, it remains uncertain how testosterone alone is able to facilitate formation of regionally specific structures such as the epididymis, vas deferens, and seminal vesicle from a straight Wolffian duct. In this study, we identified inhibin beta A (or Inhba) as a regional paracrine factor in mouse mesonephroi that controls coiling of the epithelium in the anterior Wolffian duct, the future epididymis. Inhba was expressed specifically in the mesenchyme of the anterior Wolffian duct at embryonic day 12.5 before the production of androgens. In the absence of Inhba, the epididymis failed to develop the characteristic coiling in the epithelium, which showed a dramatic decrease in proliferation. This loss of epididymal coiling did not result from testosterone deficiency, because testosterone production and parameters for testosterone action such as testis descent and anogenital distance remained normal. We further found that initial Inhba expression did not require testosterone as Inhba was also expressed in the anterior Wolffian duct of female embryos where no testosterone was produced. However, Inhba expression at later stages depended on testosterone. These results demonstrated that Inhba, a mesenchyme-specific gene, acts collectively with testosterone to facilitate epididymal coiling by stimulating epithelial proliferation.activin ͉ androgen ͉ epididymis ͉ Wolffian duct

Proper development of the seminiferous tubules (or testis cords in embryos) is critical for male fertility. Sertoli cells, somatic components of the seminiferous tubules, serve as nurse cells to the male germline, and thus their numbers decide the quantity of sperm output in adulthood. We previously identified activin A, the protein product of the activin βA (Inhba) gene, as a key regulator of murine Sertoli cell proliferation and testis cord expansion during embryogenesis. Although our genetic studies implicated fetal Leydig cells as the primary producers of testicular activin A, gonocytes are another potential source. To investigate the relative contribution of gonocyte-derived activin A to testis morphogenesis, we compared testis development in the Inhba global knockout mouse, which lacks activin A production in all cells (including the gonocytes), and a steroidogenic factor 1 (Sf1)-specific conditional knockout model in which activin A expression in testicular somatic cells is disrupted but gonocyte expression of activin A remains intact. Surprisingly, testis development was comparable in these two models of activin A insufficiency, with similar reductions in Sertoli cell proliferation and minor differences in testis histology. Thus, our findings suggest activin A from male gonocytes is insufficient to promote Sertoli cell proliferation and testis cord expansion in the absence of somatic cell-derived activin A. Evaluation of adult male mice with fetal disruption of activin A revealed reduced testis size, lowered sperm production, altered testicular histology, and elevated plasma FSH levels, defects reminiscent of human cases of androgen-sufficient idiopathic oligozoospermia.

SummaryInteractions between adjacent epithelial and mesenchymal tissues represent a highly conserved mechanism in embryonic organogenesis. In particular, the ability of the mesenchyme to instruct cellular differentiation of the epithelium is a fundamental requirement for the morphogenesis of tubular structures such as those found in the kidneys, lungs, and the developing male reproductive system. Once the tubular structure has formed, it receives signals from the mesenchyme, which can control proliferation, patterning, and differentiation of the epithelium inside the tube. However, the epithelium is not a "silent partner" in this process, and epithelium-derived factors are often required for proper maintenance of the mesenchymal compartment. Although much emphasis has been placed on the characterization of mesenchymally-derived signals required for epithelial differentiation, it is important to note that epithelial-mesenchymal interactions are a two-way street wherein each compartment requires the presence of the other for proper tubule morphogenesis and function. In this review, we discuss epithelial-mesenchymal interactions in the processes of Wolffian duct and fetal testis cord development using the mouse as a model organism and propose inhibin beta A as a conserved mesenchyme-derived regulator in these two male-specific tubular structures.

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