Structure
OSR1 is a 266 amino-acid protein and contains three C2H2 zinc finger domains. OSR1 and OSR2 share 65% amino-acid sequence and 98% zinc finger domain similarity.Function
Early expression
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''.Heart development
Mice carrying a targeted null mutation in the Odd1 gene show that Odd1 is essential for heart and intermediate mesoderm development.''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''. Deleting Osr1 in second heart field demonstrated absence of the atrial septum. It is also demonstrated that Osr1 is a direct downstream target of Tbx5 in the second heart field and establish a Tbx5-Osr1 pathway parallel to Hh signaling required for atrial septation. Osr1 can also interact with Tbx5 to regulate posterior second heart field cell cycle progression for cardiac septation.Kidney development
''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 capLimb formation
Expression of ''Osr1'' in the limb buds is initially restricted to the mesenchyme immediately below theCancer
The expression of OSR1 is more reduced in lung cancer tissues than in normal lung tissues, and was correlated with poor differentiation. OSR1 could downregulate the activity of the Wnt signaling pathway by suppressing the expression of SOX9 and β‐catenin. OSR1 expression is also significantly down-regulated at both mRNA and protein levels in primary gastric cancer tissues compared with adjacent normal tissues. It acts as a functional tumour suppressor through the transcriptional activation of p53 and repression of TCF/LEF in gastric cancer. OSR1 expression was downregulated in primary RCC and negatively correlated with histological grade. Downregulation of OSR1 might represent a potentially prognostic marker and therapeutic target for RCC.Other sites
''Osr1'' is expressed in the first and second branchial arches, in the limb buds, mouth and nasal pits, in the trunk, the forebrain., developing somites, distal mandible and developing eye.Regulation
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.Clinical relevance
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.>Orthologs
See also
OSR2 (gene)References
Further reading
* * * * *External links
* {{Transcription factors, g2 Transcription factors