RAR-related orphan receptor gamma

RAR-related orphan receptor gamma (RORγ) is a is_associated_with::protein that in humans is encoded by the RORC (RAR-related orphan receptor C) is_associated_with::gene. RORγ is member of the is_associated_with::nuclear receptor family of is_associated_with::transcription factors.

Gene expression
Two isoforms are produced from the same RORC gene, probably by selection of alternative promoters.


 * RORγ (also referred to as RORγ1) – produced from an is_associated_with::mRNA containing is_associated_with::exons 1 to 11.
 * RORγt (also known as RORγ2) – produced from an mRNA identical to that of RORγ, except that the two 5'-most exons are replaced by an alternative exon, located downstream in the gene. This causes a different, shorter is_associated_with::N-terminus.

RORγ
The is_associated_with::mRNA of the first isoform, RORγ is expressed in many tissues, including thymus, lung, liver, kidney, muscle, and brown fat. While RORγ mRNA is abundantly expressed, attempts to detect RORγ protein have not been successful therefore it is not clear whether RORγ protein is actually expressed. Consistent with this, the main is_associated_with::phenotypes identified in RORγ-/- knockout mice (where neither isoform is expressed) are those associated with RORγt immune system function and an isoform specific RORγt knockout displayed a phenotype identical to the RORγ-/- knockout. On the other hand, circadian phenotypes of RORγ-/- mice in tissues where the RORγt isoform is expressed in minute amounts argues for the expression of functional RORγ isoform. Absent protein in previous studies may be due to the high amplitude circadian rhythm of expression of this isoform in some tissues.

The mRNA is expressed in various peripheral tissues, either in a circadian fashion (e.g., in the liver and kidney) or constitutively (e.g., in the muscle).

In contrast to other ROR genes, the RORC gene is not expressed in the is_associated_with::central nervous system.

RORγt
The tissue distribution of the second isoform, RORγt, appears to be highly restricted to the is_associated_with::thymus where it is expressed exclusively in immature is_associated_with::CD4+/is_associated_with::CD8+ is_associated_with::thymocytes and in lymphoid tissue inducer (LTi) cells. RORγt inhibitors are under development for the treatment of autoimmune diseases such as is_associated_with::psoriasis and is_associated_with::rheumatoid arthritis.

Function
The RORγ protein is a DNA-binding transcription factor and is a member of the NR1 subfamily of is_associated_with::nuclear receptors. Although the specific functions of this nuclear receptor have not been fully characterized yet, some roles emerge from the literature on the mouse gene.

The RORγ isoform appears to be involved in the regulation of is_associated_with::circadian rhythms. This protein can bind to and activate the promoter of the ARNTL (BMAL1) gene, a transcription factor central to the generation of physiological circadian rhythms. Also, since the levels of RORγ are rhythmic in some tissues (liver, kidney), it has been proposed to impose a circadian pattern of expression on a number of clock-controlled genes, for example the cell cycle regulator is_associated_with::p21.

RORγt is the most studied of the two isoforms. Its best understood functionality is in the is_associated_with::immune system. The transcription factor is essential for lymphoid organogenesis, in particular is_associated_with::lymph nodes and is_associated_with::Peyer's patches, but not the is_associated_with::spleen. RORγt also plays an important regulatory role in thymopoiesis, by reducing is_associated_with::apoptosis of is_associated_with::thymocytes and promoting thymocyte differentiation into pro-inflammatory T helper 17 (Th17) cells. It also plays a role in inhibiting apoptosis of undifferentiated T cells and promoting their differentiation into Th17 cells, possibly by down regulating the expression of is_associated_with::Fas ligand and IL2, respectively.