Sall1-dependent signals affect Wnt signaling and ureter tip fate to initiate kidney development

Abstract

SUMMARYDevelopment of the metanephric kidney depends on precise control of branching of the ureteric bud. Branching events represent terminal bifurcations that are thought to depend on unique patterns of gene expression in the tip compared with the stalk and are influenced by mesenchymal signals. The metanephric mesenchyme-derived signals that control gene expression at the ureteric bud tip are not well understood. In mouse Sall1 mutants, the ureteric bud grows out and invades the metanephric mesenchyme, but it fails to initiate branching despite tip-specific expression of Ret and Wnt11. The stalk-specific marker Wnt9b and the -catenin downstream target Axin2 are ectopically expressed in the mutant ureteric bud tips, suggesting that upregulated canonical Wnt signaling disrupts ureter branching in this mutant. In support of this hypothesis, ureter arrest is rescued by lowering -catenin levels in the Sall1 mutant and is phenocopied by ectopic expression of a stabilized -catenin in the ureteric bud. Furthermore, transgenic overexpression of Wnt9b in the ureteric bud causes reduced branching in multiple founder lines. These studies indicate that Sall1-dependent signals from the metanephric mesenchyme are required to modulate ureteric bud tip Wnt patterning in order to initiate branching.

Sall1 balances self-renewal and differentiation of renal progenitor cells

“…1E); therefore, it may serve as the signal to the CM that promotes unrestrained differentiation. Consistent with this notion, constitutively active β-catenin expressed in CM results in ectopic RV formation, indicating that at high levels this signal is sufficient for nephron induction (Kiefer et al, 2010;Park et al, 2012). Our previous studies showed that increased levels of Wnt9b, similar to those observed in Sall1 mutants (Kiefer et al, 2010) (Fig.…”

“…Consistent with this notion, constitutively active β-catenin expressed in CM results in ectopic RV formation, indicating that at high levels this signal is sufficient for nephron induction (Kiefer et al, 2010;Park et al, 2012). Our previous studies showed that increased levels of Wnt9b, similar to those observed in Sall1 mutants (Kiefer et al, 2010) (Fig. 1E), was sufficient to increase expression of the RV genes Wnt4, Fgf8 and Pax8; yet this level of Wnt9b expression did not induce ectopic RVs (Kiefer et al, 2012).…”

“…By contrast, increased levels of Six2 in a transcriptional complex with Tcf/Lef, prevents differentiation induced by β-catenin. In the Sall1 mutant, Wnt9b expression is upregulated and expands to the tip of the Sall1 mutant UB (Kiefer et al, 2010) (Fig. 1E); therefore, it may serve as the signal to the CM that promotes unrestrained differentiation.…”

“…In situ hybridization was performed as previously described (Kiefer et al, 2010). Primer sequences used to produce the probes are listed in supplementary material Table S2.…”

FGF/EGF signaling regulates the renewal of early nephron progenitors during embryonic development

“…Within nephrogenic mesenchyme, expression of the Wt1 transcription factor is essential for mesenchyme survival, whereas Six2 is crucial for self-renewal and is required to suppress the premature differentiation of nephron progenitor cells (Kobayashi et al, 2008;Kreidberg et al, 1993;Self et al, 2006). Eya1, which lies upstream of Six2, is necessary for induction of the mesenchyme (Kiefer et al, 2010;Nishinakamura et al, 2001;Xu et al, 1999). Genetic inactivation of Bmp7, which is expressed both in cap mesenchyme and ureteric bud tissue, results in reduced proliferation and premature depletion of nephron progenitor cells (Blank et al, 2009;Dudley et al, 1995;Luo et al, 1995).…”