Retinoic Acid-related Orphan Receptors

Supporting information

Retinoic acid-related Orphan Receptors (RORs) are a family of orphan nuclear receptors that are believed to play a role in numerous physiological processes, including circadian rhythm and bone metabolism. The endogenous ligand for these receptors is not yet known.

Three members of the ROR family have been identified: RORα, RORβ and RORγ. RORα shows the highest expression levels in the cerebellum and thalamus, whilst RORβ is expressed in a more restricted fashion in the brain and retina. RORγ isoforms are expressed in a number of tissues, with the RORγ2 isoform being exclusively expressed in a number of immune cell types.

The expression of RORs correlates with their roles in different physiological functions. For example, RORα regulates Purkinje cell gene expression, thereby influencing Purkinje cell maturation. RORβ is crucial for rod development in the retina, and RORβ-deficient mice exhibit postnatal retinal degeneration. Mice deficient in either RORα or RORβ also exhibit abnormalities in circadian behavior.

The involvement of RORs in circadian rhythms is a consequence of their binding to ROR DNA response elements (ROREs). These elements are also bound by Rev-Erbα and Rev-Erbβ. Cross-talk between these nuclear receptor families is particularly evident when considering the expression of Bmal1, a key circadian 'clock gene' that contains two ROREs in its promoter. RORs upregulate Bmal1 expression whilst Rev-Erbs repress transcription. Bmal1/Clock or Bmal1/Npas2 heterodimers bind to promoters encoding Rev-Erbα and RORα, enhancing their expression and thus constituting a positive feedback loop. The Bmal1/Clock complex also binds to the promoters of Period (Per) and Cryptochrome (Cry) genes, which in turn inhibit Bmal1/Clock and Bmal1/Npas2 complexes. These loops of gene expression are responsible for generating circadian rhythms.

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Gene Species Gene Symbol Gene Accession No. Protein Accession No.
Retinoic acid receptor-related orphan receptor alpha Human RORA NM_134261 P35398
Mouse Rora NM_013646 P51448
Rat Rora NM_001106834 NP_001100304
Retinoic acid receptor-related orphan receptor beta Human RORB NM_006914 Q92753
Mouse Rorb NM_001043354 Q8R1B8
Rat Rorb NM_001270958 P45446
Retinoic acid receptor-related orphan receptor gamma Human RORC NM_005060 P51449
Mouse Rorc NM_011281 P51450
Rat Rorc XM_006232926 XP_006232988

Literature for Retinoic Acid-related Orphan Receptors

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