CELLULAR AND MOLECULAR MECHANISMS REGULATING POSTNATAL DEVELOPMENT OF THE UTERUS
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The uterus is essential for mammalian reproduction as it provides environment for conceptus implantation and subsequent development. Morphogenesis of the uterus is initiated in fetal life, however tissue-specific histoarchitecture is only completed postnatally including formation of endometrial glands. Endometrial glands synthesize and secrete or transport substances critical for conceptus survival and development; however, little is known about the mechanisms regulating development as well as adult function of the uterine glands. Aims of this dissertation included: identification of biological pathways involved in postnatal uterine morphogenesis and determination of the role of uterine glands in establishment of pregnancy in mice. Those objectives were addressed by: (1) conditional deletion of fibroblast growth factor receptor two (FGFR2) in the mouse uterus; (2) generation of a progesterone-induced uterine gland knockout (PUGKO) mouse model and investigation of mechanisms that underlie their infertility; (3) transcriptome profiling of microdissected luminal (LE) and glandular epithelial (GE) cells of the developing neonatal and adult mouse uterus; and (4) identification of molecular networks regulated by forkhead transcription factor box A2 (FOXA2) in the neonatal and adult uterine glands. Results of these studies established that: (1) Fgfr2 is dispensable for proper differentiation of uterine glands but plays a role in LE integrity in the adult; (2) neonatal progesterone exposure can be used as an effective method to discover pathways regulating endometrial adenogenesis and function; (3) uterine glands and their secretions have important biological roles in development of other cell types in the uterus and can affect blastocyst implantation and stromal cell decidualization; (4) FOXA2 positively regulates signaling pathways that are essential for glandular epithelial cell differentiation and development, whereas it may suppress pathways that could trigger carcinogenesis. Collectively, results of these studies provide a framework for elaborating gene regulatory networks governing development and function of uterine epithelia. Knowledge of those networks is required to facilitate the discovery of biomarkers to diagnose and treat uterine-based infertility and uterine diseases including endometriosis and endometrial cancer.