The cyclic development of the human endometrium impacts on the gynecologic health and reproductive ability of all women; disorders of this developmental process are a significant health problem. The proper development of a receptive endometrium allows for successful implantation, the limiting factor in achieving pregnancy. The molecular mechanisms that lead to proper differentiation of the endometrium are not well understood. The long term objective of this project is to define the role of HOX genes in endometrial development. HOX genes are essential regulators of embryonic development, here they assign identity to various body segments. Previous studies in mice demonstrate that targeted disruption of either the HOXA10 or HOXA11 gene leads to uterine factor infertility and failure of implantation. The PI demonstrates in preliminary data that both HOXA10 and HOXA11 show persistent expression in the adult mouse uterus and that this expression is conserved in humans. We also demonstrate that HOX10 and HOXA11 expression is menstrual cycle stage-dependent in human endometrium. HOXA10 and HOXA11 expression is dramatically upregulated in the mid-secretory phase, the time of implantation. Additionally the PI has demonstrated that sex steroids are novel direct regulators of HOX gene expression. The PI proposes that HOX genes play a role in endometrial development analogous to their role in embryonic development, regulating the cycle differentiation of the endometrium. The PI hypothesizes that changing concentrations of circulating sex steroids regulate the transcription of HOX genes in the human endometrium; changes in expression of HOX genes contribute to synchronous endometrial development and receptivity. Accordingly, the PI will characterize this expression and its regulation.
In Specific Aim I the PI will define the temporal, spatial and cellular expression patterns of HOXA10 and HOXA11 in human endometrium, and will characterize their sex steroid responsive expression in endometrial cell culture.
In Specific Aim 2 the PI will define the cis-regulatory DNA elements that mediate this expression, starting with candidate elements which have been cloned.
In Specific Aim 3 the PI will identify the essential transcription factor binding sites within these elements; the PI will also attempt to identify the trans-acting factors that bind to these sites and impart tissue specific expression. HOX genes are novel regulators of endometrial development. Regulation at the level of transcription appears to mediate this function. Characterization of HOX gene expression and its regulation will lead to an understanding of the molecular mechanisms that direct the development of this tissues, and may be expected to have clinically important implications.
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