Mullerian inhibiting substance (MIS) is essential for male sexual differentiation and fertility. Male mice that lack MIS activity retain Mullerian duct-derived tissues, including a uterus, oviducts, and a portion of the vagina and have Leydig cell hyperplasia. The majority of these male pseudohermaphrodites are infertile because the development of both male and female reproductive organs causes a physical block to the transfer of sperm into a recipient female's reproductive tract. In contrast, female mice that lack MIS activity are normal and fertile. However, female transgenic mice that ectopically express human MIS are sterile because they lack a uterus, oviducts, and ovaries, whereas a proportion of transgenic males that express very high levels of MIS appear as females because they do not masculinize due to reduced testosterone levels. Thus, in vivo studies demonstrate that correctly regulated MIS activity is essential for normal development of both male and female reproductive organs. Our objective is to define the factors that are required for the correct regulation of MIS. Biochemical and tissue culture studies have implicated the orphan nuclear receptor steroidogenic factor-1 (SF-1) and the high mobility group protein Sox9 in the regulation of MIS. However, the essential roles of these transcription factors in regulating MIS have yet to be established in vivo. We propose to use gene targeting and embryonic stem cell technologies to examine the required roles of SF-1 and Sox9 and their respective binding sites within the MIS promoter in the regulation of MIS. These in vivo studies should provide a molecular understanding of mammalian reproductive organ development.
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