HOXC and HOXD gene expression in human endometrium: Lack of redundancy with HOXA paralogs

HOXA genes, essential regulators of differentiation in the embryo, are also essential for adult cyclic endometrial development and for endometrial receptivity. Mice deficient in Hoxa10 or Hoxa11 exhibit reduced fertility because of defects in implantation. We hypothesized that HOXC10, HOXC11, HOXD10, and HOXD11, paralogs of HOXA10 and HOXA11, might also be involved in endometrial development. Here, we showed that the expression of HOXC10, HOXC11, HOXD10, and HOXD11 was evident throughout the menstrual cycle in the endometrium by semiquantitative reverse transcription-polymerase chain reaction. In the secretory phase, expression of HOXC10, HOXC11, and HOXD11 decreased to 4% and HOXD10 decreased to 25% of the proliferative phase expression (P < 0.001, P < 0.001, P < 0.02, P < 0.01, respectively). In situ hybridization demonstrated expression of each of these HOX genes primarily in the stroma and confirmed the decreased expression in the secretory phase. HOXC10, HOXC11, HOXD10, and HOXD11 expression was not regulated by sex steroids in primary endometrial stromal cells or Ishikawa cells. The expression and regulation of HOXC and HOXD genes varies from that of HOXA10 and HOXA11. Whereas HOXA10 and HOXA11 are regulators of endometrial differentiation, HOXC and HOXD genes likely regulate endometrial proliferation. Paralogous HOX genes typically have a redundant function in development; a novel evolutionary divergence of paralogous Hox genes has resulted in HOXC and HOXD genes having distinct expression patterns, regulation, and likely also distinct functions from HOXA genes. A network of HOX genes may be involved in regulating multiple aspects of endometrial development, including both proliferation and differentiation.