Osr1 Interacts Synergistically with Wt1 to Regulate Kidney Organogenesis

Abstract

Renal hypoplasia is a common cause of pediatric renal failure and several adult-onset diseases. Recent studies have associated a variant of the OSR1 gene with reduction of newborn kidney size and function in heterozygotes and neonatal lethality with kidney defects in homozygotes. How OSR1 regulates kidney development and nephron endowment is not well understood, however. In this study, by using the recently developed CRISPR genome editing technology, we genetically labeled the endogenous Osr1 protein and show that Osr1 interacts with Wt1 in the developing kidney. Whereas mice heterozygous for either an Osr1 or Wt1 null allele have normal kidneys at birth, most mice heterozygous for both Osr1 and Wt1 exhibit defects in metanephric kidney development, including unilateral or bilateral kidney agenesis or hypoplasia. The developmental defects in the Osr1+/-Wt1+/- mouse embryos were detected as early as E10.5, during specification of the metanephric mesenchyme, with the Osr1+/-Wt1+/- mouse embryos exhibiting significantly reduced Pax2-positive and Six2-positive nephron progenitor cells. Moreover, expression of Gdnf, the major nephrogenic signal for inducing ureteric bud outgrowth, was significantly reduced in the metanephric mesenchyme in Osr1+/-Wt1+/- embryos in comparison with the Osr1+/- or Wt1+/- littermates. By E11.5, as the ureteric buds invade the metanephric mesenchyme and initiate branching morphogenesis, kidney morphogenesis was significantly impaired in the Osr1+/-Wt1+/- embryos in comparison with the Osr1+/- or Wt1+/- embryos. These results indicate that Osr1 and Wt1 act synergistically to regulate nephron endowment by controlling metanephric mesenchyme specification during early nephrogenesis.

Cellular and Molecular Mechanisms of Kidney Development: From the Embryo to the Kidney Organoid

“…In the nephrogenic lineage, OSR1 expression is downregulated from the RV stage (Xu et al, 2014). OSR1 regulates the expressions of several key genes (LHX1, PAX2, EYA1, SIX2, GDNF, Cbp/p300-interacting transactivator 1 [CITED1], and Spalt like transcription factor 1 [SALL1]) in the nephrogenic mesenchyme (James, 2006;Xu et al, 2014Xu et al, , 2016. OSR1 interacts synergistically with other factors such as Wilm's tumor (WT1) and SIX2 to regulate MM specification and NPC pool maintenance (Xu et al, 2014(Xu et al, , 2016.…”

“…OSR1 regulates the expressions of several key genes (LHX1, PAX2, EYA1, SIX2, GDNF, Cbp/p300-interacting transactivator 1 [CITED1], and Spalt like transcription factor 1 [SALL1]) in the nephrogenic mesenchyme (James, 2006;Xu et al, 2014Xu et al, , 2016. OSR1 interacts synergistically with other factors such as Wilm's tumor (WT1) and SIX2 to regulate MM specification and NPC pool maintenance (Xu et al, 2014(Xu et al, , 2016. OSR1-dependent transcriptional activation of LHX1 might regulate expression of foot process and podocyte junction-associated genes that result in podocyte differentiation (Tomar et al, 2014).…”

Cellular and molecular determinants of normal and abnormal kidney development

“…It is expressed exclusively and at high levels in the differentiating MM, is downregulated upon MET during renal vesicle formation (James, Kamei, Wang, Jiang, & Schultheiss, ; Q. Wang et al, ) and it acts to regulate the expression of other transcription factors (and Gdnf itself) that are required for nephrogenesis (James et al, ; J. Xu, Liu, Chai, Lan, & Jiang, ). Mice lacking Osr1 fail to appropriately form MM (James et al, ; J. Xu et al, ), leading to failure of outgrowth and elaboration of the UB and consequently renal agenesis. Defects consistent with CAKUT are also observed in mice heterozygous for Osr1 loss of function alleles and a number of SNP variants in CAKUT patient cohorts have been identified in the gene (Fillion et al, ).…”

“…It is expressed exclusively and at high levels in the differentiating MM, is downregulated upon MET during renal vesicle formation (James, Kamei, Wang, Jiang, & Schultheiss, 2006;Q. Wang et al, 2005) and it acts to regulate the expression of other transcription factors (and Gdnf itself ) that are required for nephrogenesis (James et al, 2006;J. Xu, Liu, Chai, Lan, & Jiang, 2016).…”

Böbrek Kök Hücreleri

“…Fare embriyosunda gen haritalama, progenitör hücrelerin devamı ve diferansiyasyonu birçok belirteçin tanımlanmasına olanak sağlar. Bu belirteçler, Pax-2 ve Wt-1'in yanında Eya1, Osr1 ve Cited1'dir (15)(16)(17)(18)(19). Tanımlanmış (2).…”