Back to Search
Start Over
Osr1 Interacts Synergistically with Wt1 to Regulate Kidney Organogenesis.
- Source :
-
PloS one [PLoS One] 2016 Jul 21; Vol. 11 (7), pp. e0159597. Date of Electronic Publication: 2016 Jul 21 (Print Publication: 2016). - Publication Year :
- 2016
-
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.
- Subjects :
- Animals
Apoptosis genetics
Biomarkers metabolism
Body Patterning genetics
Cell Proliferation genetics
Embryo, Mammalian abnormalities
Embryo, Mammalian metabolism
Gene Expression Regulation, Developmental
Kidney abnormalities
Mesoderm metabolism
Mesoderm pathology
Mice, Inbred C57BL
Protein Binding
Protein Interaction Maps
Repressor Proteins genetics
Transcription Factors genetics
Ureter embryology
Ureter metabolism
WT1 Proteins
Kidney embryology
Kidney metabolism
Organogenesis genetics
Repressor Proteins metabolism
Transcription Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 11
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 27442016
- Full Text :
- https://doi.org/10.1371/journal.pone.0159597