Implantation defects are responsible for a significant percentage of pregnancy failure during natural pregnancy and in vitro fertilization procedures, yet very little is known about the molecular interactions between implanting blastocysts and the hormonally primed uterus. Two AbdominalB-like homeobox genes, Hoxa-10 and Hoxa-11, have been implicated in both uterine development and functioning of the adult uterus during implantion. Mice deficient for Hoxa-10 exhibit defects in uterine development and reduced female fertility due to defects in uterine stroma to confer uterine receptivity. During implantion, Hoxa-10 functions in a hormonally regulated pathway and likely converges with another implantation pathway involving prostaglandin E2 and its receptors. In addition, both Hoxa-10 and Hoxa-11 are required for hormonemediated stromal cell proliferation during implantation. Based on previous studies, we hypothesize that during implantation, ovarian hormones directly regulate Hoxa-10 and Hoxa-11 gene expression through binding of steroid hormone receptors to hormone response elements located in the Hoxa-10/Hoxa-11 loci. In turn Hoxa-10 and Hoxa-11 can regulate the expression of cell cycle control molecules to promote hormone-induced cellular proliferation. In addition, we hypothesize that a genetic pathway involving Hox and Wnt genes controls uterine development and exogenous hormones such as DES can affect reproductive tract development by modulating this genetic pathway. This proposal will rigorously test the above hypotheses.
Aim 1 is designed to use transgenic mice to examine the in vivo functional significance of two progesterone response elements identified in our preliminary studies.
In Aim 2, we propose to identify and characterize a DES-responsive element located in the Hoxa-11/Hoxa-10 loci. Finally in Aim 3, we propose to examine the genetic relationship between Hox and Wnt genes during uterine development and test whether DES can repress Wnt-7a expression through Hoxa-10 or Hoxa-11. Our long term goal is to use mouse as a model to study the genetic pathways controlling implantation and uterine development, which would provide us with the necessary knowledge to design better drugs to preserve natural pregnancy or to improve the in vitro fertilization protocol.
