Development and analysis of a foxa2 conditional overexpression mouse model
The uterus is essential for mammalian reproduction as it provides environment for conceptus implantation and subsequent development. Endometrial glands synthesize and secrete or transport substances critical for conceptus survival and implantation, demonstrated by the fact that female sheep and mice containing no uterine glands are infertile mainly due to impaired implantation and early pregnancy loss. FOXA2, a transcription factor, has been showed indispensable for not only the development of uterine glands in the neonate but also its differentiated function in the adult. The goal of the current study is to (1) generate a mouse model for the conditional overexpression of FOXA2, and to (2) determine the effects of FOXA2 overexpression on uterine morphogenesis and female fertility. In this thesis, Chapter 1 will review the early pregnancy of mice and discuss in detail how the early pregnancy events including blastocyst activation, uterine receptivity, apposition, attachment, penetration, stromal cell decidualization are regulated by different factors and signaling pathways. Chapter 1 will also introduce FOXA2 including its finding, structure, functions in organ development and differentiated function, functions in carcinogenesis and the regulation of its expression. Chapter 2, the research chapter, shows that we developed a mouse model which could express FOXA2 continuously only in the cells with expression of Cre recombinase. By applying two different mouse strains with special Cre expression, we found that misexpression of FOXA2 in the neonatal mouse uterus alters or inhibits normal differentiation and genesis of endometrial glands and function of the adult uterus, leading to female infertility. It also suggests that regulatory elements may localize inside the Foxa2 coding sequence and can be targeted by some unknown epigenetic mechanism. This chapter has been recently published in a journal: Endocrinology.