Homeobox genes in endometrium: from development to decidualization

Abstract

The eutherian species evolved an elaborate uterus to allow viviparity. For successful pregnancy, the uterus must not only be differentiated, but must also function optimally and any defects in uterus differentiation and/or function can lead to infertility. The homoebox gene HOXA10 has emerged to be a key player in both uterine development and its optimal functioning in adulthood. Within the Abd-B family, the posterior Hoxa genes play a dominant role in anterio-posterior segmentation of the Müllerian ducts in mammals, with Hoxa10 having a central role in uterine segmentation. In the adult endometrium, HOXA10 is expressed by endometrial cells and is regulated in a cyclic manner under the influence of ovarian steroids. During embryo implantation, expression of HOXA10 is increased in endometrial stromal cells by signals from the embryo to govern stromal cell transformation to decidual cells. Once decidualization is initiated, HOXA10 is rapidly downregulated to activate expression of pro-invasive factors to promote trophoblast invasion. We propose that HOXA10 governs embryo implantation in a three-step process: 1) acquisition of endometrial receptivity, 2) responding to signals from the blastocyst to modify receptive endometrium for decidualization 3) making the decidua conductive for trophoblast invasion and placentation. There is currently ample evidence that expression of HOXA10 is deregulated in a variety of “endometriopathies” such as endometriosis and endometrial cancers. Overall, HOXA10 appears to be the master regulator of endometrial health and a central determinant of fertility in mammals.

Vitamin D Supplementation Improves Uterine Receptivity in a Rat Model of Vitamin D Deficiency: A Possible Role of HOXA-10/FKBP52 Axis

“…In addition, it was documented that the intake of active VD in a dose-dependent way induced the upregulation of HOXA-10 gene expression in in vitro study conducted on a human endometrial stromal cell line ( Du et al, 2005 ). HOXA10 has emerged to be a key player in both uterine development and its optimal functioning in adulthood ( Ashary et al, 2020 ). Our results support the hypothesis that the VD-VDR system performs a role in the expression of HOXA-10.…”

“…Homeobox transcription factor-10 (HOXA-10), a molecular multitask protein, belongs to the homeobox family of transcription factors ( Guo et al, 2020 ) and is specifically expressed by differentiating uterine cells during the peri-implantation period ( Vitiello et al, 2008 ) as a part of regulating the decidualization process ( Ashary et al, 2020 ).…”

hsa_circ_001946 elevates HOXA10 expression and promotes the development of endometrial receptivity via sponging miR-135b

“…The expression of HOXA10 is markedly increased during the mid-secretory phase, which is indispensable for the initiation of the hyperproliferation of endometrial stromal cells [ 12 , 27 ]. We speculated that hsa_circ_001946 may affect endometrial stromal cell proliferation via regulating the level of HOXA10.…”

Modulation of endometrial E-Cadherin and N-Cadherin by ovarian steroids and embryonic stimuli

“…Thus it appears that in vivo, there could be additional factors required to induce EMT at the time of embryo invasion. Since embryo-derived factors alter the expression of genes in the luminal epithelium (Nimbkar-Joshi et al, 2012;Ashary et al, 2018Ashary et al, , 2020Laheri et al, 2018), it is tempting to propose the EMT occurring in luminal epithelium at the time of implantation could be due to embryo driven factors. Further studies will be required to address this hypothesis.…”