CELLULAR AND MOLECULAR MECHANISMS REGULATING POSTNATAL DEVELOPMENT OF THE UTERUS

Abstract

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.