Osr1 Interacts Synergistically with Wt1 to Regulate Kidney Organogenesis.
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...
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Public Library of Science (PLoS)
2016-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0159597 |
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| author | Jingyue Xu Han Liu Ok Hee Chai Yu Lan Rulang Jiang |
| author_facet | Jingyue Xu Han Liu Ok Hee Chai Yu Lan Rulang Jiang |
| author_sort | Jingyue Xu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-195a3fe29c074edea717f71c995a2877 |
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| issn | 1932-6203 |
| language | English |
| publishDate | 2016-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS ONE |
| spelling | doaj-art-195a3fe29c074edea717f71c995a28772025-08-20T02:40:27ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-01117e015959710.1371/journal.pone.0159597Osr1 Interacts Synergistically with Wt1 to Regulate Kidney Organogenesis.Jingyue XuHan LiuOk Hee ChaiYu LanRulang JiangRenal 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.https://doi.org/10.1371/journal.pone.0159597 |
| spellingShingle | Jingyue Xu Han Liu Ok Hee Chai Yu Lan Rulang Jiang Osr1 Interacts Synergistically with Wt1 to Regulate Kidney Organogenesis. PLoS ONE |
| title | Osr1 Interacts Synergistically with Wt1 to Regulate Kidney Organogenesis. |
| title_full | Osr1 Interacts Synergistically with Wt1 to Regulate Kidney Organogenesis. |
| title_fullStr | Osr1 Interacts Synergistically with Wt1 to Regulate Kidney Organogenesis. |
| title_full_unstemmed | Osr1 Interacts Synergistically with Wt1 to Regulate Kidney Organogenesis. |
| title_short | Osr1 Interacts Synergistically with Wt1 to Regulate Kidney Organogenesis. |
| title_sort | osr1 interacts synergistically with wt1 to regulate kidney organogenesis |
| url | https://doi.org/10.1371/journal.pone.0159597 |
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