Genetic Regulation of Uterine Organogenesis

Diana Alexandra Machado (Advisor: Richard R. Behringer, PhD)

          In eutherian and marsupial mammals, the site of embryo implantation and gestation is the uterus. The precursor tissue of the uterus, oviducts, cervix, and upper vagina is the Müllerian duct epithelium and its adjacent mesenchyme. Morphological uterine variation between species is established during embryogenesis by species-specific differences in Müllerian duct fusion at the midline, growth, and differentiation. For example, laboratory mice have a bipartite uterus with two uterine horns and a single cervix, whereas humans have a simplex uterus with a single chamber and single cervix. In humans, variations in the fusion process can alter typical uterine morphology, correlating with an increased incidence of infertility, high-risk pregnancy, and miscarriage. I examine the developmental genetic factors that regulate Müllerian duct development, uterine morphogenesis, and human uterine variations. It is known that Wnt7a is required for dorsal-ventral limb patterning, regression of the Müllerian ducts during male differentiation, and anterior-posterior patterning of the female reproductive tract organs. Here, I show that Wnt7a is also required for Müllerian duct fusion at the body midline to generate the bipartite uterus of the mouse. Wnt7a null female mice form Müllerian ducts, but the ducts do not fuse at the midline resulting in a didelphic reproductive tract (two separate uterine horns, two cervices, and two vaginas). Spatial transcriptome analysis of Wnt7a null and control fusion regions identified a downregulation of Hoxa13 in Wnt7a-null mesenchyme compared to wild type. Reduction in Hoxa13/HOXA13 is associated with didelphic uterine formation. These studies identify a Wnt7a-Hoxa13 genetic pathway that regulates uterine morphology.

Advisory Committee:

• Richard R. Behringer, PhD, Chair
• Yoshihiro Komatsu, PhD
• Irina V. Larina, PhD
• Rachel K. Miller, PhD
• Melinda S. Yates, PhD

Join via zoom (Please contact Ms. Machado for her Zoom meeting info.)