Hoxa11 Regulates Stromal Cell Death and Proliferation during Neonatal Uterine Development

Abstract

Increasing evidence indicates that the Hoxa11 gene plays a critical role in the proper development of the uterus. In this report, we describe potential altered cellular processes in the developing uterus of Hoxa11 mutants. Histologic analysis demonstrates normal uterine morphology in Hoxa11 mutants as compared with controls at the newborn stage and d 7 after birth. Stromal tissue was moderately reduced in the Hoxa11 mutant uterus by d 14 after birth and was absent by d 21 after birth. There is decreased cellular proliferation in the Hoxa11 mutant uterus both at 7 and 14 d after birth. Terminal deoxyribonucleotide transferase-mediated deoxyuridine triphosphate nick-end labeling analysis demonstrates that apoptosis was markedly increased in the Hoxa11 mutant uterus at d 14 after birth. p27 is decreased in the Hoxa11 mutant as evidenced by real-time PCR. Epidermal growth factor receptor expression is dramatically decreased as evidenced by both real-time PCR and immunohistochemistry results. These findings suggest that Hoxa11 is required for proper cellular proliferation and apoptotic responses in the developing neonatal uterus and that the regulation of epidermal growth factor receptor is critical to these processes.

Adaptive changes in the transcription factor HoxA-11 are essential for the evolution of pregnancy in mammals

“…The primary argument against proteinmediated evolution of gene regulatory networks is the negative pleiotropic effects of mutations that are ascribed to changes in protein-coding genes (3,4). For example, given the multiple functions of HoxA-11 in blood cell differentiation (43) and development of the body axis (44), limbs (25,45), kidney (46,47), and male (27,28) and female reproductive systems (25,27,28), it seems unlikely that a novel function could emerge in endometrial cells without simultaneously having deleterious effects in these other contexts. However, our data indicate that selection acted to maintain ancestral functions during the emergence of a novel function by recruiting amino acid sites that were previously under weak functional constraints and thus free to acquire novel functions.…”

“…The Abd-B-related Hox gene HoxA-11 is required is to activate expression of PRL (V.J.L., B.G., and G.P.W., unpublished data). In addition to its role in PRL regulation, HoxA-11 is essential for the pre-and postnatal development of the female reproductive tract and is required for successful implantation of the mammalian blastocyst (25)(26)(27)(28). Remarkably, a previous molecular evolutionary analysis of HoxA-11 suggested that an episode of positive Darwinian selection occurred in the stem-lineage of placental mammals, coincident with the origin of the uterus and pregnancy (29).…”

Candidate gene analysis in a case of congenital absence of the endometrium

“…Abnormalities in the development of mullerian structures were observed in mice with Hox gene mutations [17]. Hoxa11 mutant female mice display normal uteri at birth, but decreased cellular proliferation/increased apoptosis result in the absence of stromal tissue by day 21 after birth [18]. Hoxa11 mutant mice were sterile, likely due to reduced stromal tissue and endometrial gland development in the uteri [19, 20].…”

Some assembly required: evolutionary and systems perspectives on the mammalian reproductive system

“…HoxA-10 appears to be required for successful uterine implantation (Benson et al 1996;Lim et al 1999). Knock-outs of and mutations in HoxA-11 demonstrate that this gene is critical for female reproductive tract endometrium development, both before and after birth (Gendron et al 1997;Wong et al 2004). Other reproductive tract defects in both males and females are also seen in HoxA-11 mutants ( Hsieh- Li et al 1995).…”