The mammalian female reproductive tract, including the oviducts, uterus, and vagina, is essential for the generation of progeny and a frequent site of human disease, including infertility and cancer. The female reproductive tract is derived from the Mllerian ducts of the fetus, a pair of epithelial tubes with a surrounding mesenchyme. In mammals, two pairs of genital ducts form within the mesonephroi associated with the fetal gonads regardless of sex genotype. Initially, the Wolffian ducts form that subsequently give rise to the vas deferentia, epididymides, and seminal vesicles in males. The Wolffian ducts then guide the formation of the Mllerian ducts. The cell behaviors that regulate the elongation of the Mllerian duct are poorly understood. We will use fluorescent, time-lapse imaging of the mesonephros to determine the cell behaviors and mechanisms that lead to Mllerian duct elongation. We have shown that deletion of Lhx1, that encodes a LIM-homeodomain transcription factor, in the Mllerian duct leads to ductal loss and subsequently uterine aplasia. In the absence of the Mllerian duct the epithelial compartment, the stroma and inner myometrial layer of the uterus does not differentiate. However, the outer myometrium does form. These results highlight the intrinsic and extrinsic roles of the Mllerian duct for female reproductive tract differentiation. Emx2 and Pax2, encode transcription factors that are also expressed in the Mllerian duct and may participate in a genetic pathway of uterine development. We will test their roles in uterine development by performing Mllerian duct-specific knockouts. In males, the fetal testes produce the TGF-beta family member anti-Mllerian hormone (AMH) that binds receptors expressed in the Mllerian duct mesenchyme, causing the elimination of the Mllerian ducts. The fetal ovaries do not produce AMH, permitting Mllerian duct differentiation. Thus, mammalian fetuses are initially ambi-sexual with the potential to develop both male and female reproductive tract organs. Defects in the formation of the genital ducts and resolution of the ambi-sexual state to a male or female phenotype lead to disorders of sexual development (DSD). We have preliminary RNA-seq data that has identified candidate genes expressed in male Mllerian duct mesenchyme but not in females that may mediate AMH-induced Mllerian duct regression. The in vivo role of a subset of these candidate genes (Msx-Dlx-Osterix) will be tested by Mllerian duct mesenchyme-specific knockout. The primary objective of this proposal is to determine the molecular, cellular, and developmental mechanisms that regulate female reproductive tract organogenesis and Mllerian duct regression during male differentiation.
The proposed studies should provide fundamental insights into the molecular, cellular, and developmental mechanisms of reproductive tract organ formation in females and the signaling pathway for the elimination of the female reproductive organ progenitor tissue in males. In addition, these studies should provide new insights into the etiology of gynecological syndromes and disorders of sexual development.
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