Gata3 acts downstream of β-catenin signaling to prevent ectopic metanephric kidney induction

David Grote, Sami Kamel Boualia, Abdallah Souabni, Calli Merkel, Xuan Chi, Frank Costantini, Thomas Carroll, Maxime Bouchard

Research output: Contribution to journalArticle

83 Citations (Scopus)

Abstract

Metanephric kidney induction critically depends on mesenchymal-epithelial interactions in the caudal region of the nephric (or Wolffian) duct. Central to this process, GDNF secreted from the metanephric mesenchyme induces ureter budding by activating the Ret receptor expressed in the nephric duct epithelium. A failure to regulate this pathway is believed to be responsible for a large proportion of the developmental anomalies affecting the urogenital system. Here, we show that the nephric duct-specific inactivation of the transcription factor gene Gata3 leads to massive ectopic ureter budding. This results in a spectrum of urogenital malformations including kidney adysplasia, duplex systems, and hydroureter, as well as vas deferens hyperplasia and uterine agenesis. The variability of developmental defects is reminiscent of the congenital anomalies of the kidney and urinary tract (CAKUT) observed in human. We show that Gata3 inactivation causes premature nephric duct cell differentiation and loss of Ret receptor gene expression. These changes ultimately affect nephric duct epithelium homeostasis, leading to ectopic budding of interspersed cells still expressing the Ret receptor. Importantly, the formation of these ectopic buds requires both GDNF/Ret and Fgf signaling activities. We further identify Gata3 as a central mediator of β-catenin function in the nephric duct and demonstrate that the β-catenin/Gata3 pathway prevents premature cell differentiation independently of its role in regulating Ret expression. Together, these results establish a genetic cascade in which Gata3 acts downstream of β-catenin, but upstream of Ret, to prevent ectopic ureter budding and premature cell differentiation in the nephric duct.

Original languageEnglish (US)
Article numbere1000316
JournalPLoS Genetics
Volume4
Issue number12
DOIs
StatePublished - Dec 2008

Fingerprint

Catenins
kidneys
Kidney
anomaly
duplex
ureter
homeostasis
Ureter
bud
gene expression
defect
Glial Cell Line-Derived Neurotrophic Factor
cell differentiation
Cell Differentiation
gene
receptors
Epithelium
inactivation
Wolffian Ducts
epithelium

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Grote, D., Boualia, S. K., Souabni, A., Merkel, C., Chi, X., Costantini, F., ... Bouchard, M. (2008). Gata3 acts downstream of β-catenin signaling to prevent ectopic metanephric kidney induction. PLoS Genetics, 4(12), [e1000316]. https://doi.org/10.1371/journal.pgen.1000316

Gata3 acts downstream of β-catenin signaling to prevent ectopic metanephric kidney induction. / Grote, David; Boualia, Sami Kamel; Souabni, Abdallah; Merkel, Calli; Chi, Xuan; Costantini, Frank; Carroll, Thomas; Bouchard, Maxime.

In: PLoS Genetics, Vol. 4, No. 12, e1000316, 12.2008.

Research output: Contribution to journalArticle

Grote, D, Boualia, SK, Souabni, A, Merkel, C, Chi, X, Costantini, F, Carroll, T & Bouchard, M 2008, 'Gata3 acts downstream of β-catenin signaling to prevent ectopic metanephric kidney induction', PLoS Genetics, vol. 4, no. 12, e1000316. https://doi.org/10.1371/journal.pgen.1000316
Grote, David ; Boualia, Sami Kamel ; Souabni, Abdallah ; Merkel, Calli ; Chi, Xuan ; Costantini, Frank ; Carroll, Thomas ; Bouchard, Maxime. / Gata3 acts downstream of β-catenin signaling to prevent ectopic metanephric kidney induction. In: PLoS Genetics. 2008 ; Vol. 4, No. 12.
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