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.
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.>
^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. PMID21821672.
^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. PMID12117814.
^ abLan 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. PMID11520675.
^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. PMID16790474.
^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. PMID18804520.
^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. PMID23238298.
^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. PMID21821672.
^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. PMID22143938.
^ abTena 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.
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. PMID15761153.