Mammalian implantation is an essential step during early embryonic development and involves the synchronization of endocrine, paracrine, and cellular events which confers uterine receptivity to the early embryo. However, very little is known about the molecular interactions between implanting blastocysts and the hormonally primed uterus. Two maternally expressed AbdominalB-like homeobox genes, Hoxa-10 and Hoxa-11, have been implicated in the preparation and functioning of the implanting uterus. Mice deficient for Hoxa-10 exhibit reduced female fertility due to defects in the uterine stroma to confer uterine receptivity. Molecularly, 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 its neighboring gene Hoxa-11 have been shown to be required for hormone-mediated stromal cell proliferation during implantation. Collectively, these results place Hoxa-10 and Hoxa-11 at the top of a hormone-regulated implantation pathway and suggest that these two genes may be responsible for many hormone-induced physiological changes.
This grant proposes to test the current model, first by demonstrating in site-specific knockout mice that progesterone directly regulate Hoxa-10 and Hoxa-11 gene expression in vivo during implantation through the two putative progesterone response elements. Second, Dr. Ma will search for candidate target genes controlled by these two transcription factors, with special focus on cell cycle regulatory factors which could mediate hormone-induced cellular proliferation in the implantation uterus. Results from these experiments should contribute substantially to the understanding of the implantation process and will start the process of building a genetic pathway controlling mammalian implantation.
