Endocrine Regulation of HOX Genes

Prenatal DES exposure alters Hox gene expression

2006 Study Abstract

Hox genes have a well-characterized role in embryonic development, where they determine identity along the anteroposterior body axis. Hox genes are expressed not only during embryogenesis but also in the adult, where they are necessary for functional differentiation. Despite the known function of these genes as transcription factors, few regulatory mechanisms that drive Hox expression are known. Recently, several hormones and their cognate receptors have been shown to regulate Hox gene expression and thereby mediate development in the embryo as well as functional differentiation in the adult organism. Estradiol, progesterone, testosterone, retinoic acid, and vitamin D have been shown to regulate Hox gene expression. In the embryo, the endocrine system directs axial Hox gene expression; aberrant Hox gene expression due to exposure to endocrine disruptors contributes to the teratogenicity of these compounds. In the adult, endocrine regulation of Hox genes is necessary to enable such diverse functions as hematopoiesis and reproduction; endocrinopathies can result in dysregulated HOX gene expression affecting physiology. By regulating HOX genes, hormonal signals utilize a conserved mechanism that allows generation of structural and functional diversity in both developing and adult tissues. This review discusses endocrine Hox regulation and its impact on physiology and human pathology.

Diethylstilbestrol (DES)

In humans as in mice, gestational exposure to the synthetic nonsteroidal estrogen DES causes reproductive tract teratogenesis in female offspring. Exposed offspring also experience a high incidence of pregnancy wastage and preterm labor. It is likely that similar DES-induced posterior shifts in reproductive tract HOX expression domains occur in humans, as seen in the murine model, and may underlie the observed teratogenic defects.

DES induces altered HOX gene expression in human uterine endometrial and cervical cells resulting in robust HOXA9 mRNA expression in uterine endometrial cells and HOXA10 in uterine cervical cells. Because HOXA9 is normally expressed in the oviduct and HOXA10 in the uterus, these in vitro findings parallel the observed in vivo posterior shift in the domains of expression of the corresponding orthologs in the murine reproductive tract in response to DES exposure.

In humans, affected subjects manifest anomalies such as an abnormal T-shaped uterine cavity, possibly due to a partial transformation toward the identity of the more anteriorly located fallopian tube. It is likely that a DES-induced posterior shift in the spatial domain of HOXA9 and HOXA10 allows unopposed ectopic HOXA9 expression in the upper part of the uterus, with a consequent anterior transformation in its identity toward that of the more rostral fallopian tube. Likewise, spatially altered domains of expression of the HOX genes may also result in ectopic presence of glandular tissue in the vagina (vaginal adenosis), normally present in the uterus and cervix, predisposing such patients to the development of clear cell adenocarcinoma.

DES binds the ER, and the resultant ligand receptor complex regulates target gene expression through ERE binding. Although, the HOXA10-ERE binds both ERα and ERβ, there is differential ligand-dependent target gene activation. DES elicits significantly lower levels of HOXA10 mRNA expression compared with 17β estradiol.

During murine development, low levels of Hoxa10 mRNA detected in the midparamesonephric duct harvested from embryonic in utero DES-exposed d 16.5 animals may reflect aberrant DES-mediated Hoxa10 expression.

An interesting aspect of DES-Hoxa10 regulation is that it appears to be both qualitatively (as defined by the characteristic posterior shift in Hox spatial domains) and quantitatively (lower levels of expression) conserved in murine and human species. The pattern of HOX gene expression in the developing reproductive tract is highly conserved between species. Although the effects of DES are well described in humans and mice, it is likely that the same endocrine regulatory mechanisms are also conserved in other species; perhaps endocrine disruptors present in the environment may lead to altered Hox gene expression in a variety of wildlife. Interference of endocrine-Hox signaling may be a common mechanism of diminished reproductive success.

Sources and more information
  • Full study (free access) Endocrine Regulation of HOX Gene, Endocrine reviews, NCBI PubMed PMID: 16632680, 2006 Jun.
  • Schematic of the Hox gene clusters featured image credit nature.

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