The ROR nuclear orphan receptor subfamily: Critical regulators of multiple biological processes

The nuclear receptor superfamily, a group of structurally related, liganddependent 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 retlnoid-related orphan receptors (RORs) ct,/3, and "y comprise one nuclear orphan receptor gene subfamily.RORs exhibit a 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 response elements (ROREs) consisting of the consensus core motif AGGTCA preceded by a 5-bp A/T-rich sequence.RORE-dependent transcriptional activation by RORs is cell type-specific and mediated through interactions with nuclear cofactors.RORs have been shown to interact with certain corepressors as well as coactivators, suggesting that RORs are not constitutively active but that their activity is under some regulatory control.RORs likely can assume at least two different conformations: a repressive 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.Ca~+/calmodulin-dependent kinase IV (CaMKIV) can dramatically enhance ROR-mediated transcriptional activation.This stimulation involves CaMKIV-mediated phosphorylation not of RORs, but likely of specific nuclear cofactors that interact with RORs.RORa is widely expressed.In the cerebellum, its expression is limited to the Purkinje cells.RORc~ -/-mice and the natural RORc~-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 RORa in bone metabolism, and develop severe atherosclerosis when placed on a high-fat diet.Expression of ROR/3 is very restricted.ROR/3 is highly expressed in different parts of the neurophotoendocrine system, the pineal gland, the retina, and suprachiasmatic nuclei, suggesting a role in the control of circadian rhythm.This is by observations showing alterations in circadian behavior in ROR/3_~ upp°rted mice.ROR% which is most highly expressed in the thymus, plays an important role in thymopoiesis.Thymocytes from ROR'?-/-mice undergo accelerated apoptosis.The induction of apoptosis is, at least in part, due to a downregulation of the expression of the antiapoptotic gene BcI-XL.In addition to the thymic phenotype, ROR'y-/-mice lack lymph nodes, indicating that ROR~ is essential for lymph node organogenesis.Overexpression of RORv 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 regnlation 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 rnles in disease.