Estrogen induces retinoid receptor expression in mouse cervical epithelia

Steroid hormones and retinoids are powerful regulators of normal epithelial differentiation and function in the mouse female reproductive tract, where their actions are mediated by nuclear receptors. The expression pattern, heterodimeric interactions, and availability of ligand of these transcription factors are thought to contribute to the biological response. Estrogen (E₂) induces proliferation and squamous differentiation of the cervical and vaginal epithelium during the mouse estrous cycle, while progesterone and retinoids maintain the simple columnar epithelium of the endocervix and uterine horns. We wanted to investigate whether retinoid receptors are responsive to estrogen status during cervical epithelial differentiation induced by a single dose of estrogen in ovariectomized adult mice. Northern blot analysis demonstrated a prolonged induction of RXRα and RARγ gene expression by E₂ in the mouse cervix and vagina. When the induction of RXRα and RARγ was compared to genes known to be responsive to E₂, including estrogen receptor (ER) and c-fos, RXRα was induced within 0.5 h of hormone treatment, while RARγ induction was evident by 4 h. The induction of these retinoid receptors suggests that they may be implicated in epithelial growth and differentiation in response to E₂. Moreover, potential heterodimeric interactions among these receptors indicate that normal, cyclical epithelial differentiation results from the interplay of these molecules. Using in situ hybridization analysis, RXRα transcripts were localized preferentially in the basal cells, while ER mRNA was expressed throughout the epithelium of the ectocervix and vagina. Furthermore, ER transcripts were highly expressed in the stratified squamous foci induced by mild vitamin A depletion in the columnar epithelium of the endocervix and uterine horns. Therefore, the induction of RXRα and RARγ by E₂ and their expression pattern in relation to ER suggest that they are needed to coordinate specific genetic programs that result in cervical epithelial growth and differentiation.