Molecular and Cellular Regulation of Uterine Morphogenesis

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Project Summary In mammals, the uterus serves many functions including a passage for spermatozoa, embryo implantation, and fetal gestation. Congenital uterine anomalies are present in 25% of women with a history of miscarriage and infertility. It has been increasingly noted that uterine anomalies are simultaneously present with reproductive diseases. For this reason, it is necessary to further understand female reproductive development to better manage and prevent reproductive diseases in women. The female reproductive tract develops from a pair of epithelial tubes called the Müllerian ducts (MD). During embryonic development, the Müllerian ducts and adjacent mesenchyme differentiate into the oviducts, uterus, cervix, and upper part of the vagina. In many mammals, the MD must fuse at the midline for proper uterine morphogenesis. Formation of the uterus occurs with the differentiation, invagination, elongation, and fusion first, of the MD to the urogenital sinus (UGS) and secondly, the two MD fuse to each other at the body midline during uterine morphogenesis. Any divergence in MD fusion during human development can lead to uterine variation that may prevent a healthy pregnancy or delivery of a newborn. While there have been many studies on MD formation, it is currently unknown which genes and molecular mechanisms regulate the fusion of the MD ducts. Preliminary data from our lab shows that Wnt7a knockout mice have uterine abnormalities as a result of unfused MD, suggesting an essential role for Wnt7a in fusion of the two MD. Currently, the cellular behaviors and mechanisms that regulate MD fusion are poorly understood. The crosstalk between MD epithelium with the adjacent mesenchyme has not been studied in the context of MD fusion. In Aim 1, I will use ex vivo organ culture time-lapse imaging and immunofluorescence staining to determine which cellular changes coordinate MD fusion. In Aim 2, I will use spatial transcriptomics to identify differentially expressed genes downstream of Wnt7a, using wild-type and Wnt7a knockout embryos. The objective of this proposal is to determine the precise timing, position, and length of MD fusion, what cellular changes occur during MD fusion, and the downstream genes of Wnt7a that govern MD fusion for uterine morphogenesis. Our primary hypothesis is that Wnt7a directs the crosstalk between MD epithelium with the adjacent mesenchyme to instruct MD fusion to form a portion the uterus. The Behringer laboratory located at MD Anderson in the Texas Medical Center has expertise in reproductive biology, mammalian developmental genetics, and mouse genetic models. During my graduate training, I will meet with my Sponsor biweekly, advisory committee as a group biannually, and with experts on the subject individually as needed. I have written a chapter review and will write two first-author publications summarizing my findings. I will present my work at both my graduate program seminars and at two national conferences annually. Ultimately this work will facilitate my long-term goals of conducting my postdoctoral studies in reproductive sciences and becoming an independent reproductive biology researcher.