OSR1
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 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.
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 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, and those that become nephrons lose expression later.
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.