β-Catenin
Authors: Jacqueline Ho, Carlton M. Bates
Journal: Journal of the American Society of Nephrology (2011)

Congenital anomalies of the kidney and urinary tract are the single most common cause of renal failure in childhood. Advances in the care of children with renal failure has primarily focused on optimizing the supportive, although nonspecific, treatment of chronic kidney disease and in addressing the challenges associated with renal replacement therapies such as transplant and dialysis in this patient population. The development of novel, specific therapies has been hampered by the heterogeneity of these anomalies and wide range of prognostic outcomes. Understanding the molecular mechanisms behind these morphologic alterations would aid in developing tools that may direct prevention strategies, predict functional outcomes, or guide interventions for these children.1,2 The Wnt-signaling pathway is known to play critical roles in branching morphogenesis of the ureteric lineage, nephron induction, and mesenchymal-epithelial transition during kidney development.3–6 Secreted Wnt ligands function by activating canonical and noncanonical signaling pathways to produce their biological effects. The multifunctional protein β-catenin mediates canonical Wnt signaling through its roles in cell adhesion and as a transcriptional co-regulator for the Lef/Tcf family of transcription factors. Analyses of β-catenin reporters demonstrate transcriptional activity in the branching ureteric bud of the developing kidney,7,8 and β-catenin loss of function in the ureteric lineage results in renal aplasia or severe renal dysplasia.9,10 In this issue of JASN, Bridgewater et al.11 report that expression of stabilized β-catenin (in effect, gain of function of β-catenin) in the ureteric lineage during kidney development results in renal aplasia or severe renal hypoplasia. Furthermore, their findings implicate Tgfβ2 and the Wnt inhibitor Dkk1 as downstream effectors of this phenotype. Upregulation of Tgfβ2 in mutant kidneys and treatment of embryonic kidney explants lead to decreased ureteric branching and, interestingly, an ectopic pool of nephron progenitors as measured by Pax2 and Cited1 expression. Importantly, the authors demonstrate that the ectopic mesenchymal population is not stromal in nature. However, despite the increase in progenitor cells, the mutant kidneys have a marked decrease in nephron number. This seeming paradox is attributed to upregulation of Dkk1, resulting in an inhibition of Wnt4 activity that inhibits mesenchymal-epithelial transition of both the normal and ectopic pools of nephron progenitors5,12 and/or leads to increased apoptosis in these cell populations. Previous work by Marose et al.10 suggested that overexpression of β-catenin in the ureteric lineage results in a block in collecting duct differentiation, whereas loss of β-catenin from the ureteric lineage results in premature expression of markers of differentiated collecting duct cells. These findings are not mutually exclusive with the article by Bridgewater et al.,11 which focuses on the interaction of nephron progenitors with the ureteric bud and proposes a molecular mechanism for the observed renal dysplasia. It may be that upregulation of Tgfβ2 and/or Dkk1 in mutant ureteric tip cells acts in an autocrine manner to inhibit differentiation of collecting duct cells (in addition to the actions identified in this article). Alternatively, the two articles may have identified independent downstream effects of activated canonical Wnt signaling in the ureteric bud. One area in which the two studies seem to differ is in how stabilized β-catenin in the ureteric lineage affects the nephron progenitor pool. In contrast to the article by Bridgewater et al.,11 Marose et al.10 noted a decrease in Pax2 expression in nephron progenitors; although the reason for the discrepancy is unclear, the groups used different Hoxb7 Cre lines that may have differing levels of Cre excision in the ureteric epithelium. Bridgewater et al.11 extend their findings using an inducible model in which stabilized β-catenin is expressed in the ureteric lineage after the initial establishment of nephrogenesis and branching morphogenesis.11 Interestingly, there is a loss of committed nephron progenitors (cap mesenchyme) and developing nephrons in the mutant kidneys, with a concomitant increase in loosely organized stromal cells. The authors describe misexpression of Cited1 and Pax2 in association with upregulation of Tgfβ2 and Dkk1. In contrast to the conditional gain-of-function β-catenin model, there is decreased Pax2 expression in nephron progenitors, suggesting that there are differing effects of Tgfβ2 and Dkk1 at different developmental stages during nephrogenesis. This observation may also account for the differences observed in the report by Marose et al.10 The histologic description of the inducible mutant kidneys raises the intriguing question of whether the stromal mesenchyme is perturbed or the boundary between cap and stromal mesenchyme is maintained appropriately. The article by Bridgewater et al.,11 along with previous publications, clearly shows critical roles for β-catenin in the developing kidney.9–11,13 Although gain of function in the ureteric lineage leads to the defects outlined previously, loss of β-catenin activity results in a failure to maintain ureteric tip identity and impaired branching morphogenesis, perhaps related to premature differentiation of collecting duct cells.9,10 β-Catenin activity is also crucial in nephron progenitors, where it seems necessary and sufficient for the inductive pathways mediated by Wnt4 and Wnt9b signaling.13 Taken together, canonical Wnt signaling has distinct functions in at least two different renal lineages and at different developmental time points during renal development. To summarize, Bridgewater et al.11 propose a novel model in which stabilization of β-catenin in ureteric cells leads to inhibition of ureteric branching, an ectopic pool of nephron progenitor cells mediated by Tgfβ2, and inhibition of nephrogenesis mediated by Dkk1. These findings have significant implications for defining the pathogenesis of human renal dysplasia of multiple etiologies and mouse models of renal dysplasia, which are known to overexpress β-catenin.14,15 Increased canonical Wnt signaling may represent a common pathway that is triggered by a primary insult in renal dysplasia and subsequently serves to propagate aberrant renal development. This report lays the basis for future experiments to define the common molecular pathways involved in the pathogenesis of renal dysplasia and provide insights that may lead to the development of innovative molecular tools to predict outcomes or guide interventions in children with renal failure. DISCLOSURES None.