THE MULLERIAN INHIBITOR AND MAMMALIAN SEXUAL DEVELOPMENT

The elegant embryological experiments of Jost demonstrated the existen ce of a foetal testicular factor that is required to cause the regress ion of the Mullerian duct system, the anlagen of the uterus, oviducts and upper portion of the vagina, during male sexual development. The M ullerian inhibitor currently known as Mullerian-inhibiting substance ( MIS) or anti-Mullerian hormone (AMH), is a member of the transforming growth factor-beta (TGF-beta) family of growth and differentiation fac tors. The genetic manipulation of the mouse germline has lead to the g eneration of animal models for MIS function. Female transgenic mice th at chronically express MIS during embryogenesis are born without a ute rus or oviducts and their ovaries lose germ cells and degenerate, reca pitulating the phenotype of the bovine freemartin. Same male transgeni c mice from very high MIS-expressing lines are feminized, suggesting a lterations in androgen biosynthesis. Male mice homozygous for a target ed mutation of the MIS gene develop as male pseudohermaphrodites with both male (testes and Wolffian duct-derived) and female (Mullerian duc t-derived) reproductive organs. Most are infertile because the develop ment of two reproductive systems physically blocks the exit of sperm f rom these males. In addition, Leydig cell hyperplasia is detected in a proportion of these males and in one case a Leydig cell tumour was fo und. Recently, a gene encoding a TGF-beta family type II Ser/Thr kinas e membrane-bound receptor has been isolated that is expressed in both male and female gonads and in the mesenchyme surrounding the Mullerian ducts during embryogenesis. These findings suggest that MIS-mediated Mullerian duct regression occurs indirectly through mesenchymal tissue . A targeted mutation of this receptor has been established in the mou se germline. Mice homozygous for this receptor mutation should be usef ul in understanding the MIS signalling pathway for Mullerian duct regr ession and gonadal function.