| Nuclear retinoic acid (RA) receptors (RARs) consist of three subtypes encoded by separate genes: α (NR1B1), β (NR1B2), and γ (NR1B3). For each subtype, there are at least two isoforms, which are generated by differential promoter usage and alternative splicing and differ only in their N-terminal regions. Retinoids, which are metabolites of vitamin A, serve as ligands for RARs. RARs function as ligand-dependent transcriptional regulators and are found to be heterodimerized with retinoid X receptors (RXRs). These transcriptionally active dimers regulate the expression of genes involved in cellular differentiation, proliferation, and apoptosis. Consequently, RARs play critical roles in a variety of biological processes, including development, reproduction, immunity, and organogenesis. RAR mutations, fusion proteins, altered expression levels, or aberrant post-translational modifications result in multiple diseases due to altered RAR function and disruption of homeostasis. In contrast to the ubiquitously expressed RARα subtype, RARγ displays a complex tissue-specific expression pattern. The hematopoietic system expresses significant levels of RARγ, and a recent study identified a role for RARγ in hematopoietic stem cell maintenance. RARγ is the predominant subtype in human and mouse epidermis, representing 90% of the RARs in this tissue. Given the high level of RARγ expression in the skin, it has been suggested that this nuclear receptor participates in a transcriptional program that governs maintenance and differentiation of normal epidermis and skin appendages. The transcriptional activity of RARγ is under stringent control, in part, through retinoic acid-induced phosphorylation and proteasomal degradation. |
