MULLERIAN-INHIBITING SUBSTANCE FUNCTION DURING MAMMALIAN SEXUAL DEVELOPMENT

To investigate the role of Mullerian-inhibiting substance (MIS) in mam malian sexual development, we generated MIS-deficient mice. Although M IS-deficient males had testes that were fully descended and produced f unctional sperm, they also developed female reproductive organs, which interfered with sperm transfer into females, rendering most of these males infertile. Their testes had Leydig cell hyperplasia and, in one instance, neoplasia. The actions of the two primary hormones of male s exual differentation were genetically eliminated using the testicular feminization (Tfm) mutation in combination with the MIS mutant allele. XY Tfm/MIS double mutants developed as females, with a uterus, coiled oviducts, and no male reproductive organs except undescended dysfunct ional testes. These results suggest that eliminating the presumptive f emale reproductive tract in male fetuses facilitates fertility and tha t in testes MIS is a negative regulator of Leydig cell proliferation. Eliminating the presumptive male reproductive tract is necessary for p roper oviductal morphogenesis during female mouse development.