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.

Lgr4‐deficient mice showed premature differentiation of ureteric bud with reduced expression of Wnt effector Lef1 and Gata3

“…During the development of metanephric kidneys, DBA is downregulated in ureteric tip cells (Michael et al, 2007;Grote et al, 2008;Marose et al, 2008). Here, DBA staining performed on metanephric kidney at E15.5 showed that the Lgr4 À/À tips of UB were clearly positive in comparison with the Lgr4 þ/þ tips (n>4) (Fig.…”

“…Grote et al (2008) have proposed a genetic cascade in which Gata3 acts downstream of b-catenin to prevent premature cell differentiation and they also have reported that Gata3 acts independently of Ret to maintain the cells in an undifferentiated state (Grote et al, 2008 (Fig. 5A).…”

“…Additional genetic studies in mice have further revealed a critical role for the b-catenin/Gata3 signaling pathway, which maintains the epithelial cells in an undifferentiated state in UB and prevents inappropriate responses to signals promoting UB differentiation (Grote et al, 2008;Marose et al, 2008;Schmidt-Ott and Barasch, 2008). Hoxb7-Cre mediated removal of b-catenin from the mouse UB/Wolffian duct epithelium leads to the premature expression of gene products normally associated with the differentiated kidney collecting duct system including the water channel protein, Aquaporin-3 (Aqp3), and the tight junction protein isoform, ZO1aþ.…”

“…Reciprocally, expression of a stabilized form of b-catenin appears to block differentiation of the ducts (Marose et al, 2008;Schmidt-Ott and Barasch, 2008). Grote et al (2008) have reported that Gata3 inactivation with Hoxb7-Cre causes premature nephric duct cell differentiation and loss of Ret expression, and they have further identified Gata3 as a mediator of b-catenin function and demonstrated that the b-catenin/Gata3 pathway prevents premature cell differentiation. Interestingly, no difference in DBA and Zo1þ expression levels can be observed between wild-type and Ret-deficient embryos leading Grote et al to conclude that Gata3 acts independently of Ret to maintain an undifferentiated state in the duct epithelium (Grote et al, 2008).…”

“…Grote et al (2008) have reported that Gata3 inactivation with Hoxb7-Cre causes premature nephric duct cell differentiation and loss of Ret expression, and they have further identified Gata3 as a mediator of b-catenin function and demonstrated that the b-catenin/Gata3 pathway prevents premature cell differentiation. Interestingly, no difference in DBA and Zo1þ expression levels can be observed between wild-type and Ret-deficient embryos leading Grote et al to conclude that Gata3 acts independently of Ret to maintain an undifferentiated state in the duct epithelium (Grote et al, 2008). Although some genetic studies on the function for maintaining the UB/Wolffian duct in an undifferentiated state have been reported as described above, the mechanisms that prevent the inappropriate differentiation of the duct remains largely unknown.…”