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The Role of TGFβ Signaling and Epigenetic Regulators in the Female Reproductive Tract
Abstract
Mechanisms governing the female reproductive tract development and function are incompletely defined. Transforming growth factor β (TGFβ) superfamily signaling regulates multifaceted reproductive processes. TGFβ ligands signal through the TGFβ receptor type 2 (TGFBR2)/TGFBR1 complex. As TGFBR2 and TGFBR1 form a signaling complex upon ligand stimulation, they are expected to be equally important for propagating TGFβ signaling that elicits cellular responses. However, several genetic studies challenge this concept and indicate that disruption of TGFBR2 or TGFBR1 may lead to contrasting phenotypic outcomes. The first aim was to determine the functional requirement of TGFBR2 in the female reproductive tract and the potential phenotypic divergence/similarity resulting from conditional ablation of either receptor. It was found that conditional deletion of Tgfbr2 led to a similar phenotype to that of Tgfbr1 deletion in the female reproductive tract. Furthermore, genetic removal of both Tgfbr1 and Tgfbr2 in the uterus had minimal impact on the phenotype of Tgfbr2 conditional knockout mice. These results reveal the functional similarity between TGFBR2 and TGFBR1 in maintaining the structural integrity of the female reproductive tract. The second aim was to determine the role of two functionally distinct epigenetic regulators, the methyltransferase enhancer of zeste homology 2 (EZH2) and lysine (K)-specific demethylase 6A (KDM6A), in uterine development and function. Uterine glands together with their secretions are potential regulators of maternal receptivity, implantation, and fetal development. However, little is known about the epigenetic regulation of uterine gland development. We generated mice with conditional deletion of Ezh2 using Amhr2-Cre. Strikingly, these mice showed marked developmental defects in postnatal uterine glands, corroborated by findings from both histochemical analysis and 3D imaging. Accompanied with the deficient uterine adenogenesis was impaired embryo development. RNA-sequencing revealed dysregulation of genes associated with signaling pathways that play fundamental roles in development and disease. In contrast, loss of KDM6A impaired decidual development and led to pregnancy failure. These studies reveal important roles of epigenetic regulators in normal uterine development and pregnancy success.
Citation
Ni, Nan (2022). The Role of TGFβ Signaling and Epigenetic Regulators in the Female Reproductive Tract. Doctoral dissertation, Texas A&M University. Available electronically from https : / /hdl .handle .net /1969 .1 /197800.