The in vivo roles of müllerian-inhibiting substance.

The fetal testis functions as the sex differentiator by imposing a masculine pattern of development upon a genetic program that is inherently female. Two hormones produced by the fetal testis mediate the differentiation of the müllerian and Wolffian ducts (Figs. 1 and 4). MIS actively inhibits the development of the müllerian ducts, and testosterone induces the differentiation of the Wolffian ducts. The absence of these two hormones during fetal development in the female (the hormonal equivalent of no testes) permits müllerian duct differentiation and does not induce Wolffian duct development. The in vivo outcomes of ectopic MIS exposure or MIS deficiency illustrate the balance required to coordinately differentiate and cause regression of the respective male and female genital ducts. The observations made in the MIS-deficient mice demonstrate that codevelopment of both genital duct systems interferes with normal development of both systems and ultimately interferes with reproduction and fertility. Thus, reproduction and fertility in mammals appear to be most efficient if only one type of genital duct system develops. The phenotypes of the MIS-overexpressing transgenic mice and the MIS-deficient mice are similar yet different. Some of the explanations that might reconcile these differences probably lie with the receptor for MIS. Since the MIS-overexpressing transgenic mice are exposed to pharmacological levels of MIS during development, it seems possible that this may lead to productive interactions with other related receptors. Candidate genes have been isolated for the MIS receptor that are membrane-bound serine/threonine kinases (Baarends et al., 1994; di Clemente et al., 1994) similar to those cloned for the TGF-beta (Lin et al., 1992) and activin (Mathews and Vale, 1991) type II receptors. Interestingly, expression of these putative MIS receptor genes is localized by in situ hybridization to the mesenchymal cells adjacent to the müllerian ducts, suggesting that MIS most likely alters the surrounding mesenchyme to elicit müllerian duct regression. Experiments are underway to isolate the mouse MIS receptor gene to thereby generate MIS receptor-deficient mice and to compare the phenotype with the MIS gain-of-function and loss-of-function animals. Isolation of the human MIS receptor gene will facilitate the identification of human PMDS patients with normal levels of MIS that have mutations in the MIS receptor gene. Finally, studies of the MIS receptor gene will open up avenues for the molecular characterization of signal transduction pathways that mediate müllerian duct regression and Leydig cell proliferation control.