{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n IRX5 is a homeobox transcription factor with diverse functions in development and tissue homeostasis. In adipose tissue, increased IRX5 expression—mediated by obesity‐risk alleles at the FTO locus—suppresses mitochondrial thermogenesis in adipocyte precursors, thereby shifting the balance from energy‐dissipating beige adipocytes to lipid‐storing white adipocytes and promoting obesity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the heart, IRX5 is essential for establishing proper repolarization and conduction. It represses the expression of the Kv4.2 potassium channel in endocardial myocardium to create a gradient of repolarizing currents that is crucial for coordinated electrical activity. Loss of IRX5 results in increased Kv4.2 levels, alteration of action potential dynamics, and heightened susceptibility to arrhythmias."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n During embryogenesis, IRX5 contributes to the morphogenesis of multiple organs. It modulates the migration of progenitor cells in branchial arches and gonads—acting via transcriptional repression of critical signaling molecules—to coordinate craniofacial, brain, and gonadal development. Disruption of IRX5 function in this context is associated with a congenital syndrome that affects the face, brain, blood, heart, bone, and gonads."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond developmental roles, IRX5 activity influences cellular proliferation and survival in cancer. For instance, in prostate cancer, down-regulation of IRX5 by 1,25-dihydroxyvitamin D3 leads to increased p21 levels, G2-M arrest, and apoptosis, suggesting that modulation of IRX5 may be a potential therapeutic target."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the skeletal system, IRX5 acts downstream of WNT signaling to regulate cell fate decisions in hypertrophic chondrocytes, promoting their transition toward osteoblasts rather than adipocytes, which is important for maintaining bone homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, in the hypothalamus, IRX5—together with IRX3—regulates postnatal neurogenesis. Reduced dosage of these factors enhances the generation of leptin-responsive arcuate neurons, thereby lowering food intake and contributing to energy balance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings underscore the multifaceted roles of IRX5 in transcriptional regulation across metabolic, cardiac, developmental, skeletal, and oncogenic contexts.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Melina Claussnitzer, Simon N Dankel, Kyoung-Han Kim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "FTO Obesity Variant Circuitry and Adipocyte Browning in Humans."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "N Engl J Med (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1056/NEJMoa1502214"}], "href": "https://doi.org/10.1056/NEJMoa1502214"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26287746"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26287746"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Mathias Rask-Andersen, Markus Sällman Almén, Helgi B Schiöth "}, {"type": "b", "children": [{"type": "t", "text": "Scrutinizing the FTO locus: compelling evidence for a complex, long-range regulatory context."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Genet (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00439-015-1599-5"}], "href": "https://doi.org/10.1007/s00439-015-1599-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26340902"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26340902"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Danny L Costantini, Eric P Arruda, Pooja Agarwal, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The homeodomain transcription factor Irx5 establishes the mouse cardiac ventricular repolarization gradient."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2005.08.004"}], "href": "https://doi.org/10.1016/j.cell.2005.08.004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16239150"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16239150"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Nathalie Gaborit, Rui Sakuma, John N Wylie, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cooperative and antagonistic roles for Irx3 and Irx5 in cardiac morphogenesis and postnatal physiology."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Development (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/dev.081703"}], "href": "https://doi.org/10.1242/dev.081703"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22992950"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22992950"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Carine Bonnard, Anna C Strobl, Mohammad Shboul, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in IRX5 impair craniofacial development and germ cell migration via SDF1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng.2259"}], "href": "https://doi.org/10.1038/ng.2259"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22581230"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22581230"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Isabelle Anselme, Christine Laclef, Magali Lanaud, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Defects in brain patterning and head morphogenesis in the mouse mutant Fused toes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dev Biol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ydbio.2006.12.025"}], "href": "https://doi.org/10.1016/j.ydbio.2006.12.025"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17241623"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17241623"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Anne Myrthue, Brooks L S Rademacher, Janet Pittsenbarger, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The iroquois homeobox gene 5 is regulated by 1,25-dihydroxyvitamin D3 in human prostate cancer and regulates apoptosis and the cell cycle in LNCaP prostate cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-07-4649"}], "href": "https://doi.org/10.1158/1078-0432.CCR-07-4649"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18519790"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18519790"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Zhijia Tan, Mingpeng Kong, Songjia Wen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "IRX3 and IRX5 Inhibit Adipogenic Differentiation of Hypertrophic Chondrocytes and Promote Osteogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Bone Miner Res (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jbmr.4132"}], "href": "https://doi.org/10.1002/jbmr.4132"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32662900"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32662900"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Joe Eun Son, Zhengchao Dou, Kyoung-Han Kim, et al. 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