GENETIC-ANALYSIS OF THE MULLERIAN-INHIBITING SUBSTANCE SIGNAL-TRANSDUCTION PATHWAY IN MAMMALIAN SEXUAL-DIFFERENTIATION

Mullerian-inhibiting substance (MIS) is a member of the transforming g rowth factor-beta (TGF-beta) gene family. MIS expression in males caus es the regression of the Mullerian ducts, an essential process in male sexual differentiation. Recently, an MIS type II receptor gene has be en isolated that is expressed during embryogenesis in mesenchymal cell s adjacent to the Mullerian duct epithelium and in Sertoli and granulo sa cells of the fetal and adult, male and female gonads, respectively. MIS receptor mutant males develop as internal pseudohermaphrodites, p ossessing a complete male reproductive tract and also a uterus and ovi ducts, a phenocopy of MIS ligand-deficient male mice. They express bot h MIS mRNA and protein, showing that ligand was present, but target or gans were hormone-insensitive. All produce sperm, but the majority wer e infertile because the presence of their female reproductive organs b locks sperm transfer into females. Focal seminiferous tubule atrophy a ccompanied by Leydig cell hyperplasia was observed and began as early as 2 months of age. The phenotype of MIS ligand/MIS receptor double mu tant males was indistinguishable from those of each single mutant. MIS receptor/alpha-inhibin double mutant males developed testicular strom al tumors and large fluid-filled uteri that were identical in phenotyp e to MIS ligand/alpha-inhibin double mutant males. These studies provi de in vivo evidence that MIS is the only ligand of the MIS type II rec eptor, in contrast to the complexity of other TGF-beta gene family sig naling pathways.