Two genes of the Hoxa cluster, Hoxa10 and Hoxa11, are expressed in localized areas of the paramesonephric duct destined to become the uterus or the lower uterine segment and cervix, respectively. Hoxa10 and Hoxa11 gene expression is necessary for endometrial development, allowing uterine receptivity to implantation. Female Hoxa10 (-/-) or Hoxa11 (-/-) homozygous mutant mice have uterine factor infertility. Although these mice ovulate normally, they are unable to support implantation. Embryos from Hoxa10 (-/-) mice successfully implant in pseudopregnant wild-type surrogates; however, wild-type embryos do not implant in Hoxa10- or Hoxa11-deficient uterus.
In addition to regulating the embryonic development of the uterus, Hoxa10 and Hoxa11 have specific roles in endometrial development in the adult. Blocking maternal Hoxa10 expression in the adult uterus of wild-type mice with antisense blocks implantation, demonstrating the necessity of adult expression. HOXA10 and HOXA11 are regulated by estrogen and progesterone in the adult human endometrium where their expression rises dramatically in the midsecretory phase, which is at the time of implantation, and remains elevated throughout the rest of the secretory phase. Human conditions associated with decreased implantation demonstrate diminished endometrial Hoxa10 and Hoxa11 expression.