Retinoids are powerful regulators of epithelial differentiation and are essential for its maintenance. Because retinoids are necessary for cervical epithelial differentiation, they have been used as chemopreventive agents of cervical dysplasia and neoplasia. We were interested in determining whether different cervical epithelial phenotypes express specific retinoid receptors. The cervical epithelium contains the two phenotypes, stratified squamous and simple columnar, which join at the squamocolumnar junction. In addition, the simple columnar epithelium undergoes squamous metaplasia in response to vitamin A deficiency. Therefore, the cervical epithelium is suitable to study the expression pattern of the retinoid receptors in the three phenotypes, simple columnar, stratified squamous, and squamous metaplastic, simultaneously. The distribution pattern of the major retinoic acid receptor (RAR) isoforms (α 1, α 2, β 2, β 3, γ 1, and γ 2) and retinoid-X receptors (RXR α, -β, and -γ) was studied by in situ hybridization. At the tissue level, RAR α (1 and 2) and RXR (α and β) transcripts and, to a lesser extent, RAR γ (1 and 2) transcripts were associated with the cervical stratified squamous subjunctional epithelium. The simple columnar epithelium, which is highly responsive to vitamin A status, expressed high levels of RAR α (1 and 2), RAR β (2 and 3), and RXR (α and β) transcripts. Only RAR β (2 and 3) and RXR (α and β) transcripts were down-modulated by the condition of vitamin A deficiency and expressed less in squamous metaplastic foci than the simple columnar epithelium. RXR γ was undetectable in all three cervical epithelia. At the cellular level, basal and suprabasal expression was found for RARs, and preferential localization of RXRs was seen in basal cells. RXRs are auxiliary proteins for a variety of other nuclear receptors with which they form heterodimers, including RARs. The fact that RXRs are mainly localized in basal and columnar cells of the cervix suggests the need for the regulation and diversity generated by potential heterodimeric interactions in these rapidly proliferating cells in vivo. The unique pattern of expression and localization of the RARs and RXRs in different cervical epithelial tissues and cell types supports the hypothesis that they perform specific functions in cervical epithelial differentiation. This is in contrast to the major isoforms of each RAR, which have similar patterns of expression in the different cervical epithelial phenotypes and cell types, suggesting a redundancy in function.
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