RAR-related orphan receptor alpha (RORα), also known as NR1F1 (nuclear receptor subfamily 1, group F, member 1) is a nuclear receptor that in humans is encoded by the RORA gene. RORα participates in the transcriptional regulation of some genes involved in circadian rhythm. In mice, RORα is essential for development of cerebellum through direct regulation of genes expressed in Purkinje cells. It also plays an essential role in the development of type 2 innate lymphoid cells (ILC2) and mutant animals are ILC2 deficient. In addition, although present in normal numbers, the ILC3 and Th17 cells from RORα deficient mice are defective for cytokine production. Discovery The first three-human isoforms of RORα were initially cloned and characterized as nuclear receptors in 1994 by Giguère and colleagues, when their structure and function were first studied. In the early 2000s, various studies demonstrated that RORα displays rhythmic patterns of expression in a circadian cycle in the liver, kidney, retina, and lung. Of interest, it was around this time that RORα abundance was found to be circadian in the mammalian suprachiasmatic nucleus. RORα is necessary for normal circadian rhythms in mice, demonstrating its importance in chronobiology. Structure The protein encoded by this gene is a member of the NR1 subfamily of nuclear hormone receptors. In humans, 4 isoforms of RORα have been identified, which are generated via alternative splicing and promoter usage, and exhibit differential tissue-specific expression. The protein structure of RORα consists of four canonical functional groups: an N-terminal (A/B) domain, a DNA-binding domain containing two zinc fingers, a hinge domain, and a C-terminal ligand-binding domain. Within the ROR family, the DNA-binding domain is highly conserved, and the ligand-binding domain is only moderately conserved. Different isoforms of RORα have different binding specificities and strengths of transcriptional activity. Regulation of circadian rhythm The core mammalian circadian clock is a negative feedback loop which consists of Per1/Per2, Cry1/Cry2, Bmal1, and Clock. This feedback loop is stabilized through another loop involving the transcriptional regulation of Bmal1. Transactivation of Bmal1 is regulated through the upstream ROR/REV-ERB Response Element (RRE) in the Bmal1 promoter, to which RORα and REV-ERBα bind. This stabilizing regulatory loop itself is induced by the Bmal1/Clock heterodimer, which induces transcription of RORα and REV-ERBα. RORα, which activates transcription of Bmal1, and REV-ERBα, which represses transcription of Bmal1, compete to bind to the RRE. This feedback loop regulating the expression of Bmal1 is thought to