Pleiotropic effects of Hoxa10 on the functional development of peri-implantation endometrium

Hoxa10, a homeodomain transcription factor, is dynamically expressed in adult uterine endometrium where it is necessary for embryo implantation. Endometrial Hoxa10 expression is driven by estrogen and progesterone. High levels of endometrial Hoxa10 expression coincide with high progesterone levels and development of endometrial receptivity. Although, progesterone is sufficient for endometrial differentiation and implantation, the molecular mechanisms by which progesterone mediates endometrial receptivity are not known. To determine if Hoxa10 mediates the developmental effects of progesterone in the endometrial cell compartments, we performed in vivo uterine transfection using pcDNA3.1/Hoxa10 in estrogen-primed, ovariectomized mice and compared results to mice treated with progesterone. Additional control mice were treated with either estrogen alone or empty vector pcDNA3.1. By using ovariectomized mice, we were able to determine specific developmental effects resultant from Hoxa10 treatment and distinguish them from those mediated by the regulation of multiple endogenous genes (including Hoxa10) by ovarian progesterone. Treatment with either Hoxa10 or progesterone resulted in diminished uterine weight and increased expression of characteristic cell-type specific differentiation markers such as epithelial calcitonin and stromal prolactin, suggesting that Hoxa10 likely mediates progesterone induced functional differentiation of endometrial epithelium and stroma. However, progesterone treatment suppressed endometrial eosinophil infiltration and degranulation compared to that seen with Hoxa10 treatment. Besides mediating progestational effects, Hoxa10 may activate distinct developmental pathways leading to endometrial differentiation. Functional differentiation in regenerative adult tissues may depend on timed expression of embryonic selector genes.