Gata3 Acts Downstream of β-Catenin Signaling to Prevent Ectopic Metanephric Kidney Induction

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.

Author Summary

In humans, kidney development originates during embryonic development by the sprouting of an epithelial bud—called the ureteric bud—from a simple epithelial structure—the nephric duct. The ureteric bud quickly grows and branches in a treelike fashion to form the kidney collecting duct system, while the emerging ureteric tips induce nephron differentiation. One of the most important steps during kidney development is the positioning of a single ureteric bud along the nephric duct, since mutations of genes implicated in this process lead to severe urogenital malformations. In this study, we identified the Gata3 protein as a crucial regulator of ureteric bud positioning by using genetically modified mice. Deleting the Gata3 gene in the mouse resulted in the development of multiple kidneys emerging at improper positions. We show that this defect was caused by a hypersensitivity of nephric duct cells in their response to local growth signals. Interestingly, this phenomenon was partly triggered by premature differentiation of a subset of nephric duct cells. Furthermore, we report a genetic pathway in which Wnt/β-catenin signaling activates the Gata3 gene, which in turn positively regulates the Ret gene. In summary, we introduce a mouse model system that can be used to study human birth defects affecting the urogenital system.