Loss of function of two or more adjacent, paralogous, or similarly expressed Hox genes has repeatedly demonstrated exacerbations of phenotype compared with the single mutants, often unmasking phenotypes not evident after single mutation of any of the genes involved. Loss of function of one member of the paralogous group results in hypo-morphic phenotypes. These observations suggest functional redundancy among the Hox genes, such that inactivation of one gene can be compensated by the activity of other Hox genes, which share sequences or have similar domains of expression.
Here, we demonstrate that HOXC and HOXD genes likely are not redundant to HOXA genes in the endometrium. HOXCIO, HOXC11, HOXDIO, and HOXD11 are expressed at high levels in the proliferative phase, and their expression decreases in the secretory phase. HOXAIO and HOXA11 are both up-regulated by sex steroids in the mid-luteal phase. Our data suggest a lack of direct sex-steroid effect on HOXCIO, HOXC11, HOXDIO, and HOXD11 mRNA abundance in the endometrium. Unlike HOX redundancy in embryonic development, this differential adult expression suggests distinct functions. This novel lack of redundancy in the adult uterus suggests that in eutherian species Hox paralogs function has diverged with the evolution of distinct methods of reproduction. The duplication of Hox clusters may have allowed for evolution of adult reproductive tract plasticity and novel functions such as an estrous cycle.