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 M?llerian 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 M?llerian ducts. The cell behaviors that regulate the elongation of the M?llerian duct are poorly understood. We will use fluorescent, time-lapse imaging of the mesonephros to determine the cell behaviors and mechanisms that lead to M?llerian duct elongation. We have shown that deletion of Lhx1, that encodes a LIM-homeodomain transcription factor, in the M?llerian duct leads to ductal loss and subsequently uterine aplasia. In the absence of the M?llerian 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 M?llerian duct for female reproductive tract differentiation. Emx2 and Pax2, encode transcription factors that are also expressed in the M?llerian duct and may participate in a genetic pathway of uterine development. We will test their roles in uterine development by performing M?llerian duct-specific knockouts. In males, the fetal testes produce the TGF-beta family member anti-M?llerian hormone (AMH) that binds receptors expressed in the M?llerian duct mesenchyme, causing the elimination of the M?llerian ducts. The fetal ovaries do not produce AMH, permitting M?llerian 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 M?llerian duct mesenchyme but not in females that may mediate AMH-induced M?llerian duct regression. The in vivo role of a subset of these candidate genes (Msx-Dlx-Osterix) will be tested by M?llerian 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 M?llerian 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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