Protein odd-skipped-related 1 is a transcription factor that in humans is encoded by the OSR1 gene. The OSR1 and OSR2 transcription factors participate in the normal development of body parts such as the kidney.
Protein odd-skipped related 1 is a zinc-finger transcription factor that, in humans, is encoded by the OSR1 gene found on chromosome 2 (2p24.1) and in mice is encoded by the Osr1 gene. In mammals, OSR1 is involved in the development of the kidneys, heart and in the palate and is often coexpressed with OSR2. OSR1 and OSR2 are homologous to the Odd-skipped class transcription factors in Drosophila, encoded by odd, bowl, sob and arm.
In mice, during gastrulation on embryological day 7.5, cells fated to become intermediate mesoderm show the mouse OSR1 homologue, Osr1, expression. A day later, it is expressed in the intermediate mesoderm, lateral to the neural plate. Osr1 expression weakens and shifts posteriorly, to the presumptive kidneys, by day 9.5. By day 10.5, the branchial arch and limbs also begin to express Osr1.
Osr1 regulates atrial septum formation in the heart. Osr1 is expressed in the dorsal atrial wall, from which the primary atrial septum will emerge, and later in the septum and left venous valve leaflet. It is also present in the mesothelium of the thoracic cavity and the parietal pericardium. Embryos lacking Osr1 expression usually die before birth due to deformed atrioventricular junctions and hypoplastic venous valves; the ones that progress to term also have an incomplete parietal pericardium. These pathologies occur in the presence of other transcription factors important for atrial septum formation such as Nkx2.5, Pitx2 and Tbx5.
Osr1 is the earliest marker of the intermediate mesoderm, which will form the gonads and kidneys. This expression is not essential for the formation of intermediate mesoderm but for the differentiation towards renal and gonadal structures. Osr1 acts upstream of and causes expression of the transcription factors Lhx1, Pax2 and Wt1 which are involved in early urogenital development. In normal kidney development, activation of the Pax2-Eya1-Hox11 complex and subsequent activation of Six2 and Gdnf expression allows for branching of the ureteric bud and maintenance of the nephron-forming cap mesenchyme. Six2 maintains the self-renewing state of the cap mesenchyme. and Gdnf, via the Gdnf-Ret signalling pathway, is required for attraction and branching of the growing ureteric bud. Within the developing kidney, Osr1 expressing cells will become mesangial cells, pericytes, ureteric smooth muscle and the kidney capsule. The cell types that Osr1 expressing cells will differentiate into are determined by the timing of loss of expression – cells that will become part of the vasculature or ureteric epithelium lose expression of Osr1 early (E8.5), and those that become nephrons lose expression later (E11.5). All three stages of kidney formation are affected in mice lacking Osr1 expression and are similar to mice with reduced Wt1 and Pax2 expression – the Wollfian duct is abnormal, there are fewer mesonephric tubules and the kidney-forming metanephros and gonads are missing. In embryonic day 10.5, embryos lacking Osr1 expression fail to grow a ureteric bud that migrates into the uncompacted metanephric mesenchyme. The lack of inductive signals from the ureteric bud combined with a downstream reduction in Pax2 expression results in apoptosis and agenesis of the kidney.
Expression of Osr1 in the limb buds is initially restricted to the mesenchyme immediately below the endoderm, but shifts anteriorly and proximally by embryonic day 11.5. In mice, Osr1 is expressed in the interdigital mesenchyme and presumptive synovial joints during limb development. where it overlaps with expression of Gdf5, an early marker for joint formation.
The expression of Osr1 is negatively regulated by Runx2 and Ikzf1. These genes are involved in osteoblast and lymphocyte differentiation through their interaction with the Osr1 promoter region. In human osteoblast and osteosarcoma cell lines, OSR1 is directly induced by 1,25-dihydroxyvitamin D3.
Reduction of kidney size caused by variant allele
A variant human OSR1 allele which does not produce a functional transcript and found in 6% of Caucasian populations, reduces the size of the newborn kidney by 11.8%.
OSR1 methylation in cancer
OSR1 is methylated and downregulated in 51.8% of gastric cancer cells and tissues. When expressed normally, OSR1 is anti-proliferative – it induces cell cycle arrest and induces apoptosis in gastric cancer cell. OSR1 is methylated in above 85% of squamous cell carcinomas.>
|Chick||cOsr1||Expressed in intermediate and lateral plate mesoderm, developing sinus venosus of the heart, maxillary and mandibular processes, developing eye and limbs.|
|Xenopus frog||XOsr||Expressed in the intermediate mesoderm and required in pronephros formation.|
|Danio rerio Zebrafish||zOsr||Pronephros formation. Reduced zOsr expression results in reduced expression of kidney epithelial sodium-glucose cotransporter and sodium-potassium-chlorine cotransporter genes.|
- Coulter DE, Swaykus EA, Beran-Koehn MA, Goldberg D, Wieschaus E, Schedl P (November 1990). "Molecular analysis of odd-skipped, a zinc finger encoding segmentation gene with a novel pair-rule expression pattern". The EMBO Journal. 9 (11): 3795–804. PMC 552139. PMID 2120051.
- Katoh M (August 2002). "Molecular cloning and characterization of OSR1 on human chromosome 2p24". International Journal of Molecular Medicine. 10 (2): 221–5. doi:10.3892/ijmm.10.2.221. PMID 12119563.
- "Entrez Gene: OSR1 odd-skipped related 1 (Drosophila)".
- Zhang Z, Iglesias D, Eliopoulos N, El Kares R, Chu L, Romagnani P, Goodyer P (November 2011). "A variant OSR1 allele which disturbs OSR1 mRNA expression in renal progenitor cells is associated with reduction of newborn kidney size and function". Human Molecular Genetics. 20 (21): 4167–74. doi:10.1093/hmg/ddr341. PMID 21821672.
- Hart MC, Wang L, Coulter DE (1996). "Comparison of the structure and expression of odd-skipped and two related genes that encode a new family of zinc finger proteins in Drosophila". Genetics. 144 (1): 171–82. PMC 1207491. PMID 8878683.
- Green RB, Hatini V, Johansen KA, Liu XJ, Lengyel JA (2002). "Drumstick is a zinc finger protein that antagonizes Lines to control patterning and morphogenesis of the Drosophila hindgut". Development. 129 (15): 3645–56. PMID 12117814.
- Wang L, Coulter DE (1996). "bowel, an odd-skipped homolog, functions in the terminal pathway during Drosophila embryogenesis". The EMBO Journal. 15 (12): 3182–96. PMC 450261. PMID 8670819.
- So PL, Danielian PS (1999). "Cloning and expression analysis of a mouse gene related to Drosophila odd-skipped". Mechanisms of Development. 84 (1–2): 157–60. doi:10.1016/s0925-4773(99)00058-1. PMID 10473132.
- Lan Y, Kingsley PD, Cho ES, Jiang R (2001). "Osr2, a new mouse gene related to Drosophila odd-skipped, exhibits dynamic expression patterns during craniofacial, limb, and kidney development". Mechanisms of Development. 107 (1–2): 175–9. doi:10.1016/s0925-4773(01)00457-9. PMID 11520675.
- Wang Q, Lan Y, Cho ES, Maltby KM, Jiang R (2005). "Odd-skipped related 1 (Odd 1) is an essential regulator of heart and urogenital development". Developmental Biology. 288 (2): 582–94. doi:10.1016/j.ydbio.2005.09.024. PMC 3869089. PMID 16223478.
- James RG, Kamei CN, Wang Q, Jiang R, Schultheiss TM (2006). "Odd-skipped related 1 is required for development of the metanephric kidney and regulates formation and differentiation of kidney precursor cells". Development. 133 (15): 2995–3004. doi:10.1242/dev.02442. PMID 16790474.
- Gong KQ, Yallowitz AR, Sun H, Dressler GR, Wellik DM (2007). "A Hox-Eya-Pax complex regulates early kidney developmental gene expression". Molecular and Cellular Biology. 27 (21): 7661–8. doi:10.1128/MCB.00465-07. PMC 2169072. PMID 17785448.
- Self M, Lagutin OV, Bowling B, Hendrix J, Cai Y, Dressler GR, Oliver G (2006). "Six2 is required for suppression of nephrogenesis and progenitor renewal in the developing kidney". The EMBO Journal. 25 (21): 5214–28. doi:10.1038/sj.emboj.7601381. PMC 1630416. PMID 17036046.
- Costantini F (2006). "Renal branching morphogenesis: concepts, questions, and recent advances". Differentiation; Research in Biological Diversity. 74 (7): 402–21. doi:10.1111/j.1432-0436.2006.00106.x. PMID 16916378.
- Mugford JW, Sipilä P, McMahon JA, McMahon AP (2008). "Osr1 expression demarcates a multi-potent population of intermediate mesoderm that undergoes progressive restriction to an Osr1-dependent nephron progenitor compartment within the mammalian kidney". Developmental Biology. 324 (1): 88–98. doi:10.1016/j.ydbio.2008.09.010. PMC 2642884. PMID 18835385.
- Stricker S, Brieske N, Haupt J, Mundlos S (2006). "Comparative expression pattern of Odd-skipped related genes Osr1 and Osr2 in chick embryonic development". Gene Expression Patterns. 6 (8): 826–34. doi:10.1016/j.modgep.2006.02.003. PMID 16554187.
- Gao Y, Lan Y, Liu H, Jiang R (2011). "The zinc finger transcription factors Osr1 and Osr2 control synovial joint formation". Developmental Biology. 352 (1): 83–91. doi:10.1016/j.ydbio.2011.01.018. PMC 3057278. PMID 21262216.
- Yamauchi M, Kawai S, Kato T, Ooshima T, Amano A (2008). "Odd-skipped related 1 gene expression is regulated by Runx2 and Ikzf1 transcription factors". Gene. 426 (1–2): 81–90. doi:10.1016/j.gene.2008.08.015. PMID 18804520.
- Verlinden L, Kriebitzsch C, Eelen G, Van Camp M, Leyssens C, Tan BK, Beullens I, Verstuyf A (2013). "The odd-skipped related genes Osr1 and Osr2 are induced by 1,25-dihydroxyvitamin D3". The Journal of Steroid Biochemistry and Molecular Biology. 136: 94–7. doi:10.1016/j.jsbmb.2012.12.001. PMID 23238298.
- Zhang Z, Iglesias D, Eliopoulos N, El Kares R, Chu L, Romagnani P, Goodyer P (2011). "A variant OSR1 allele which disturbs OSR1 mRNA expression in renal progenitor cells is associated with reduction of newborn kidney size and function". Human Molecular Genetics. 20 (21): 4167–74. doi:10.1093/hmg/ddr341. PMID 21821672.
- Otani K, Dong Y, Li X, Lu J, Zhang N, Xu L, Go MY, Ng EK, Arakawa T, Chan FK, Sung JJ, Yu J (2014). "Odd-skipped related 1 is a novel tumour suppressor gene and a potential prognostic biomarker in gastric cancer". The Journal of Pathology. 234 (3): 302–15. doi:10.1002/path.4391. PMC 4277686. PMID 24931004.
- Rauch TA, Wang Z, Wu X, Kernstine KH, Riggs AD, Pfeifer GP (2012). "DNA methylation biomarkers for lung cancer". Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine. 33 (2): 287–96. doi:10.1007/s13277-011-0282-2. PMID 22143938.
- Tena JJ, Neto A, de la Calle-Mustienes E, Bras-Pereira C, Casares F, Gomez-Skarmeta JL (2007). "Odd-skipped genes encode repressors that control kidney development". Dev Biol. 301: 518–31. doi:10.1016/j.ydbio.2006.08.063.
- Hartley JL, Temple GF, Brasch MA (November 2000). "DNA cloning using in vitro site-specific recombination". Genome Research. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
- Simpson JC, Wellenreuther R, Poustka A, Pepperkok R, Wiemann S (September 2000). "Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing". EMBO Reports. 1 (3): 287–92. doi:10.1093/embo-reports/kvd058. PMC 1083732. PMID 11256614.
- Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A (October 2004). "From ORFeome to biology: a functional genomics pipeline". Genome Research. 14 (10B): 2136–44. doi:10.1101/gr.2576704. PMC 528930. PMID 15489336.
- Barrios-Rodiles M, Brown KR, Ozdamar B, Bose R, Liu Z, Donovan RS, Shinjo F, Liu Y, Dembowy J, Taylor IW, Luga V, Przulj N, Robinson M, Suzuki H, Hayashizaki Y, Jurisica I, Wrana JL (March 2005). "High-throughput mapping of a dynamic signaling network in mammalian cells". Science. 307 (5715): 1621–5. doi:10.1126/science.1105776. PMID 15761153.
- Mehrle A, Rosenfelder H, Schupp I, del Val C, Arlt D, Hahne F, Bechtel S, Simpson J, Hofmann O, Hide W, Glatting KH, Huber W, Pepperkok R, Poustka A, Wiemann S (January 2006). "The LIFEdb database in 2006". Nucleic Acids Research. 34 (Database issue): D415–8. doi:10.1093/nar/gkj139. PMC 1347501. PMID 16381901.
- Chicago Tribune’s Trine Tsouderos Undermines OSR Antioxidant