Gao, Yang (2017-08). Understanding the Role of Transforming Growth Factor Beta Signaling in the Uterus Using Genetically Modified Mouse Models. Doctoral Dissertation. Thesis uri icon

abstract

  • Transforming growth factor beta (TGF?) superfamily signaling regulates multiple reproductive events. However, the in vivo role of the TGF? signaling in uterine development and function is not well defined. Conditional knockout (cKO) of TGF? receptor 1 (TGFBR1) in the female reproductive tract leads to remarkable smooth muscle defects. The first study of this dissertation research was to further define the role of TGF? signaling in uterine development. We found that the myometrial defects in Tgfbr1 cKO mice were associated with dysregulated expression of key extracellular matrix components and platelet-derived growth factors signaling during a critical time window of early postnatal uterine development. To complement the loss of function model, in the second study, we generated a uterine specific gain-of-function mouse model harboring a constitutively active TGFBR1 which leads to over-activation of TGF? signaling. Constitutive activation of TGFBR1 caused infertility and defects in uterine morphology and function, as evidenced by abnormal myometrial structure, dramatically reduced numbers of uterine glands, and impaired uterine decidualization. These studies underscore the importance of a balanced TGF? signaling system in establishing a uterine microenvironment conducive to normal development and function. In the third study of this dissertation research, we focused on identifying the role of TGF? signaling in PTEN-inactivated uterine epithelial cells. Depletion of PTEN in the mouse uterus causes endometrial cancer. We found that simultaneous deletion of Tgfbr1 and Pten in the mouse uterus caused severe endometrial lesions and pulmonary metastases compared with deletion of Pten alone. The development of metastasis and accelerated tumor progression in the Pten/Tgfbr1 double knockout mice was linked to increased production of pro-inflammatory chemokines, enhanced cancer cell motility evidenced by myometrial invasion and disruption, and an altered tumor microenvironment characterized by recruitment of tumor-associated macrophages. Our results suggest that TGF? signaling synergizes with PTEN to suppress the progression of endometrial cancer.

publication date

  • August 2017