{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nOSR1 is a zinc‐finger transcription factor originally characterized through bioinformatic and cDNA‐based cloning approaches and is defined by three conserved C2H2‐type zinc fingers and a key tyrosine phosphorylation site, features that are evolutionarily conserved from Drosophila to humans."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In developmental contexts, OSR1 is critical for maintaining mesenchymal progenitor populations and orchestrating organogenesis. For example, in human kidney formation, splicing variants of OSR1 are associated with reduced nephron progenitor pools, smaller kidney volumes, and altered renal function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In the developing heart, OSR1 cooperates with TBX5 in the second heart field to regulate atrial septation via downstream effectors such as Pcsk6."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Moreover, studies in mice have shown that diminished Osr1 expression leads to urinary tract anomalies—including vesicoureteric reflux and hydronephrosis—as well as aberrant Müllerian duct development that manifests as uterine hypoplasia and endometrial defects"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ";."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Complementary observations suggest that polymorphic variants of developmental regulatory genes like OSR1 may predispose to congenital malformations."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its developmental roles, OSR1 functions as a tumor suppressor in several human cancers. Downregulation of OSR1 expression—often mediated by promoter hypermethylation—has been documented in lung, gastric, renal, and ovarian cancers. Experimental restoration of OSR1 in lung cancer cells, for instance, suppresses proliferation and invasion through modulation of the Wnt/β‐catenin pathway and reduction of pro‐oncogenic targets such as SOX9."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In gastric cancer models, OSR1 reactivation leads to p53 pathway activation, cell cycle arrest, and apoptosis, highlighting its role in cellular homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Similarly, in renal cell carcinoma, OSR1 loss reduces the expression of tumor suppressor genes within the p53 signaling cascade and enhances oncogenic gene expression"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ", and in ovarian cancer, OSR1 overexpression suppresses tumor growth and metastasis partly through the transcriptional upregulation of FSTL1."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond developmental and tumor‐suppressive roles, OSR1 is also implicated in the regulation of ion homeostasis. Acting within the WNK kinase signaling cascade, OSR1 binds to specific sequence motifs in inward rectifier potassium channels (such as Kir2.1 and Kir2.3) to promote their plasma membrane localization and modulate cellular ion transport and volume regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Masaru Katoh "}, {"type": "b", "children": [{"type": "t", "text": "Molecular cloning and characterization of OSR1 on human chromosome 2p24."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Med (2002)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12119563"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12119563"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Zhao Zhang, Diana Iglesias, Nicoletta Eliopoulos, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A variant OSR1 allele which disturbs OSR1 mRNA expression in renal progenitor cells is associated with reduction of newborn kidney size and function."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddr341"}], "href": "https://doi.org/10.1093/hmg/ddr341"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21821672"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21821672"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Ke K Zhang, Menglan Xiang, Lun Zhou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Gene network and familial analyses uncover a gene network involving Tbx5/Osr1/Pcsk6 interaction in the second heart field for atrial septation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddv636"}], "href": "https://doi.org/10.1093/hmg/ddv636"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26744331"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26744331"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Marie-Lyne Fillion, Jasmine El Andalousi, Fatima Tokhmafshan, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "OSR1 disruption contributes to uterine factor infertility via impaired Müllerian duct development and endometrial receptivity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI161701"}], "href": "https://doi.org/10.1172/JCI161701"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37847567"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37847567"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Bernarda Lozić, Vjekoslav Krželj, Ivana Kuzmić-Prusac, et al. 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