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Abstract
To investigate the role of Müllerian-inhibiting substance (MIS) in mammalian sexual
development, we generated MIS-deficient mice. Although MIS-deficient males had testes
that were fully descended and produced functional 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 sexual differentiation
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 dysfunctional
testes. These results suggest that eliminating the presumptive female reproductive
tract in male fetuses facilitates fertility and that in testes MIS is a negative regulator
of Leydig cell proliferation. Eliminating the presumptive male reproductive tract
is necessary for proper oviductal morphogenesis during female mouse development.