Essential roles of inhibin beta A in mouse epididymal coiling

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Abstract
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.