{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T22:42:25Z","timestamp":1792104145750,"version":"4.4.0"},"reference-count":153,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,5,3]],"date-time":"2024-05-03T00:00:00Z","timestamp":1714694400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>The retinoic acid-related orphan receptor alpha (ROR\u03b1) protein first came into the limelight due to a set of staggerer mice, discovered at the Jackson Laboratories in the United States of America by Sidman, Lane, and Dickie (1962) and genetically deciphered by Hamilton et\u00a0al. in 1996. These staggerer mice exhibited cerebellar defects, an ataxic gait, a stagger along with several other developmental abnormalities, compensatory mechanisms, and, most importantly, a deletion of 160 kilobases (kb), encompassing the <jats:italic>ROR\u03b1<\/jats:italic> ligand binding domain (LBD). The discovery of the staggerer mice and the subsequent discovery of a loss of the LBD within the <jats:italic>ROR\u03b1<\/jats:italic> gene of these mice at the genetic level clearly indicated that ROR\u03b1\u2019s LBD played a crucial role in patterning during embryogenesis. Moreover, a chance study by Roffler-Tarlov and Sidman (1978) noted reduced concentrations of glutamic acid levels in the staggerer mice, indicating a possible role for the essence of a nutritionally balanced diet. The sequential organisation of the building blocks of intact genes, requires the nucleotide bases of deoxyribonucleic acid (DNA): purines and pyrimidines, both of which are synthesized, upon a constant supply of glutamine, an amino acid fortified in a balanced diet and a byproduct of the carbohydrate and lipid metabolic pathways. A nutritionally balanced diet, along with a metabolic \u201cenzymatic machinery\u201d devoid of mutations\/aberrations, was essential in the uninterrupted transcription of ROR\u03b1 during embryogenesis. In addition to the above, following translation, a ligand-responsive ROR\u03b1 acts as a \u201cmolecular circadian regulator\u201d during embryogenesis and not only is expressed selectively and differentially, but also promotes differential activity depending on the anatomical and pathological site of its expression. ROR\u03b1 is highly expressed in the central nervous system (CNS) and the endocrine organs. Additionally, <jats:italic>ROR\u03b1<\/jats:italic> and the <jats:italic>clock<\/jats:italic> genes are core components of the circadian rhythmicity, with the expression of <jats:italic>ROR\u03b1<\/jats:italic> fluctuating in a night\u2013day\u2013night sigmoidal pattern and undoubtedly serves as an endocrine-like, albeit \u201cmolecular\u2013circadian regulator\u201d. Melatonin, a circadian hormone, along with tri-iodothyronine and some steroid hormones are known to regulate ROR\u03b1-mediated molecular activity, with each of these hormones themselves being regulated rhythmically by the hypothalamic\u2013pituitary axis (HPA). The HPA regulates the circadian rhythm and cyclical release of hormones, in a self-regulatory feedback loop. Irregular sleep\u2013wake patterns affect circadian rhythmicity and the ability of the immune system to withstand infections. The staggerer mice with their thinner bones, an altered skeletal musculature, an aberrant metabolic profile, the ataxic gait and an underdeveloped cerebellar cortex; exhibited compensatory mechanisms, that not only allowed the survival of the staggerer mice, but also enhanced protection from microbial invasions and resistance to high-fat-diet induced obesity. This review has been compiled in its present form, more than 14\u00a0years later after a chromatin immunoprecipitation (ChIP) cloning and sequencing methodology helped me identify signal transducer and activator of\u00a0transcription 5 (STAT5) target sequences, one of which was mapped to the first\u00a0intron of the <jats:italic>ROR\u03b1<\/jats:italic> gene. The 599-base-long sequence containing one consensus TTCNNNGAA (TTCN<jats:sub>3<\/jats:sub>GAA) gamma-activated sequence (GAS) and five other non-consensus TTN<jats:sub>5<\/jats:sub>AA sequences had been identified from the clones isolated from the STAT5 target sites (fragments) in human phytohemagglutinin-activated CD8+ T lymphocytes, during my doctoral studies between 2006 and 2009. Most importantly, preliminary studies noted a unique <jats:italic>ROR\u03b1<\/jats:italic> expression profile, during a time-course study on the ribonucleic acid (RNA), extracted from human phytohemagglutinin (PHA) activated CD8+ T lymphocytes stimulated with interleukin-2 (IL-2). This review mainly focuses on the \u201cstaggerer mice\u201d with one of its first roles materialising during embryogenesis, a molecular-endocrine mediated circadian-like regulatory process.<\/jats:p>","DOI":"10.3389\/fendo.2023.1300729","type":"journal-article","created":{"date-parts":[[2024,5,3]],"date-time":"2024-05-03T06:01:09Z","timestamp":1714716069000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["RAR-related orphan receptor alpha and the staggerer mice: a fine molecular story"],"prefix":"10.3389","volume":"14","author":[{"given":"Aradhana","family":"Rani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,5,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1126\/science.137.3530.610","article-title":"Staggerer, a new mutation in the mouse affecting the 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