The nuclear receptor superfamily, a group of structurally related, ligand-dependent transcription factors, includes a large number of orphan receptors for which no ligand has yet been identified. These proteins function as key regulators of many physiological processes that occur during embryonic development and in the adult. The retinoid-related orphan receptors (RORs) α, β, and γ comprise one nuclear orphan receptor gene subfamily. RORs exhibit modular structure that is characteristic for nuclear receptors; the DNA-binding domain is highly conserved and the ligand-binding domain is moderately conserved among RORs. By a combination of alternative promoter usage and exon splicing, each ROR gene generates several isoforms that differ only in their amino terminus. RORs bind as monomers to specific ROR preceded by a 5-bp A/T-rich specific and mediated through interactions with nuclear cofactors. RORs have been shown to interact with certain corespressors as well as coactivators, suggesting the RORs are not constitutively active but that their activity is under some regulatory control. state, which allows interaction with corepressor complexes, and an active state, which promotes binding of coactivator complexes. Whether the transition between these two states is regulated by ligand binding and/or by phosphorylation remains to be determined. Ca2+/calmodulin-dependent kinase IV (CaMKIV) can dramatically enhance ROR-mediated transcriptional activation. This stimulation involves CaMKIV-mediated phosphorylation not of RORs, but ikely of specific nuclear cofactors that interact with RORs. RORα is widely expressed. in the cerebellum, its expression is limited to the Purkinje cells. RORα-1- mice and the natural RORα-deficient staggerer mice exhibit severe cerebellar ataxia due to a defect in Purkinje cell development. In addition, these mice have thin long bones, suggesting a role for RORα in bone metabolism, and develop severe atherosclerosis when placed on a high-fat diet. Expression of RORβ is very restricted. RORβ is highly expressed in different parts of the neurophotoendocrine system, the pineal gland, the retina, and suprachiasmatic nuclei, suggesting a rle in the control of circadian rhythm. This is supported by observations showing alterations in circadian behavior in RORβ-1- mie. RORγ, which is most highly expressed in the thymus, plays an important role in thymopoiesis. Thymocytes from RORγ-1- mice undergo accelerated apoptosis. The induction of apoptosis is, at least in part, due to a down-regulation of the expression of the antiapoptotic gene Bcl-XL. In addition to the thymic phenotype, RORγ-1- mice lack lymph nodes, indicating that RORγ is essential for lymph node organogenesis. Overexpresion of RORγ has been shown to inhibit T cell receptor-mediated apoptosis in T cell hybridomas and to repress the induction of Fas-ligand and interleukin 2. These studies demonstrate that RORs play critical roles in the regulation of a variety of physiological processes. Further characterization of the mechanisms of action of RORs will not only lead to the identification of ROR target genes and provide additional insight into their normal physiological functions, but will also determine their roles in disease. © 2001.