WNT/b-catenin signaling in nephron progenitors andtheir epithelial progenyKai M. Schmidt-Ott1,2 and Jonathan Barasch3

1Max-Delbruck Center for Molecular Medicine, Berlin, Germany; 2Department of Nephrology and Hypertension, Charite Berlin, CampusBuch, Experimental and Clinical Research Center, HELIOS Klinikum-Berlin, Berlin, Germany and 3Department of Medicine, ColumbiaUniversity College of Physicians and Surgeons, New York, New York, USA

WNT signaling is a fundamental molecular pathway in

both embryogenesis and disease. Nephron development

is dependent on WNT signaling. The nephron epithelia

proximal to the collecting duct develop from progenitor

cells in the metanephric mesenchyme. The process involves

formation of proto-epithelial cell aggregates, conversion into

epithelia, and proximal-distal patterning of the nephron. Two

ligands from the WNT family, namely Wnt9b and Wnt4, are

required for nephron differentiation. Recent studies have

addressed the downstream targets of these WNT ligands and

delineated the role of the canonical WNT signaling pathway.

This pathway depends on the intracellular protein b-catenin

and the T cell-specific transcription factor/lymphoid enhancer

factor-1 (TCF/Lef1) family of transcription factors. Selective

b-catenin signaling antagonism inhibits differentiation of

metanephric mesenchymal progenitor cells, while

forced activation triggers a stage progression towards

proto-epithelial aggregates. Nonetheless, activation of the

pathway is transient during epithelial differentiation and

titration of pathway activity may be central for the proper

coordination of differentiation and morphogenesis. We

review current evidence on the WNT/b-catenin/TCF/Lef1

signaling pathway in kidney epithelial development

and discuss the potential implication of non-canonical

WNT signaling and WNT-independent events.

Kidney International (2008) 74, 1004–1008; doi:10.1038/ki.2008.322;

published online 16 July 2008

KEYWORDS: metanephric mesenchyme; ureteric bud; canonical WNT

signaling; nephron differentiation; b-catenin; TCF/Lef1 transcription factors

The Wolffian duct sends off a dorsal branch called theureteric bud to initiate mammalian kidney development.This epithelial structure invades an adjacent blastemalprogenitor cell population called the metanephric mesen-chyme. The ureteric bud receives signals from the meta-nephric mesenchyme to undergo branching morphogenesisand develop into the ureter and collecting duct system.Reciprocally, the metanephric mesenchyme receives signalsfrom the branching tips of the ureteric bud, which facilitateits survival, cellular proliferation, and condensation intoproto-epithelial clusters termed pretubular aggregates, thedirect renal epithelial precursors. Additional events mediateproximal–distal patterning and terminal differentiation ofthese progenitors into all nephron epithelia proximal to thecollecting duct.1,2 The process of nephron differentiationfrom epithelial progenitors is recapitulated in vitro when themetanephric mesenchyme is isolated from rat or mouseembryos and placed in an organ culture in the presence ofinductive factors. These inductive factors that were originallyderived from the ureteric bud or embryonic spinal cord havenow been characterized more closely on a molecular level.2–8

Remarkably, an activation of the WNT (after the Drosophilahomolog Wingless and the Int-1 [Wnt1] integration site invirally induced murine breast tumors) signaling pathwayappears to be common to all these inducers.2,9,10

WNT SIGNALING PATHWAYS

Since their discovery in the 1980s, WNT proteins have beenfound to be involved in a number of cell type-specificprocesses governing development and homeostasis. WNTproteins belong to a highly conserved family of secretedgrowth factors that contain roughly 20 members inmammals. Although different members of the WNT familyhave been identified based on their amino-acid homology,they display a substantial divergence in their biological effectson target cells. Intracellular WNT signaling is classified into‘canonical’ and ‘non-canonical’ pathways. In this context,these terms refer to whether or not the signaling pathway isb-catenin-dependent (canonical) or b-catenin-independent(non-canonical).

b-Catenin is a multifunctional intracellular protein thatis characterized by a core domain containing 12 copies of a

m i n i r e v i e w http://www.kidney-international.org

& 2008 International Society of Nephrology

Received 26 March 2008; accepted 29 April 2008; published online

16 July 2008

Correspondence: Kai M. Schmidt-Ott, Max-Delbruck-Center for Molecular

Medicine, Robert-Rossle-Strasse 10, 13125 Berlin, Germany.

E-mail: kai.schmidt-ott@mdc-berlin.de

1004 Kidney International (2008) 74, 1004–1008

42-amino-acid ‘armadillo’ motif, named after the Drosophilaortholog of b-catenin. These repeats generate a positivelycharged groove that facilitates b-catenin interaction withseveral negatively charged ligands, including adenomatouspolyposis coli and TCF/Lef1 transcription factors.11 Inaddition to its intracellular signaling functions, b-cateninconstitutes a central component of adherens junctions, whereit interacts with cadherins and a-catenin.12 A multiproteincomplex called the ‘b-catenin destruction complex’ cancapture intracellular b-catenin by default (Figure 1). Thiscomplex contains the proteins axin, adenomatous poly-posis coli, and glycogen synthase kinase 3b (GSK3b), whichphosphorylates b-catenin on several N-terminal serine/threonine residues. Phosphorylated b-catenin is then ubiqui-tinated and targeted for proteasomal degradation. Therefore,in the absence of WNT signaling, intracellular b-catenin levelsare kept low through continuous degradation. Once acanonical WNT ligand binds to a FZD (Frizzled)/LRP(lipoprotein receptor-related protein) receptor complex onthe cell surface, the b-catenin destruction complex isinhibited through mechanisms that involve the intracellularprotein Dishevelled. Consequently, b-catenin is no longerphosphorylated by GSK3b, escapes degradation, accumulatesin the cytoplasm, and is translocated to the nucleus.There b-catenin interacts with transcription factors of theTCF/Lef1 family displacing transcriptional repressors of theTLE/Groucho family. Thereby, b-catenin converts TCF/Lef1factors from transcriptional repressors into transcriptionalactivators. By this rather linear transduction cascade,WNT ligands act as extracellular switches that turn on celltype-specific transcriptional programs in their target cells,which in turn mediate the biological effects of canonicalWNT signaling.12,13

The non-canonical branches of WNT signaling have beenidentified more recently.14 Notably, WNT signals have beenimplicated in the organization of proximal–distal epithelialcell polarity across a sheet or tube, a process termed planarcell polarity (PCP).14,15 Components of the WNT/PCPpathway also include Frizzled receptors and Dishevelled,but they are independent of b-catenin stabilization andTCF/Lef1 signaling. Instead, WNT/PCP signaling involvesthe GTPases RhoA and Rac1 as well as Jun N-terminalkinase. Different WNT ligands have been reported to elicitdifferential activity on these signaling branches. For instance,Wnt3a and Wnt1 signal through the b-catenin/TCF/Lef1pathway in most cell types, whereas Wnt5a and Wnt11 havebeen associated with non-canonical pathways. However, evenfor these well-characterized family members, the activityappears to be context- and cell type-dependent.16

WNT LIGANDS INVOLVED IN RENAL EPITHELIALDIFFERENTIATION

At least two WNT ligands, Wnt9b and Wnt4, are intimatelyinvolved in the epithelial differentiation of metanephricmesenchymal progenitors. Wnt9b is produced by the uretericbud and its genetic deletion in mice leads to severe kidneyhypoplasia, which is related, at least in part, to an arrest ofprogenitor cell differentiation in the metanephric mesench-yme.7 In Wnt9b mutant mice, the metanephric mesenchymeis present; however, it fails to undergo the first step ofdifferentiation, namely formation of the pretubular aggre-gate. As a result, the characteristic marker molecules of thisstructure, such as Pax8, Fgf8, and Lhx1, are absent.

A second WNT ligand, Wnt4, is placed downstream ofWnt9b signaling. The Wnt4 expression domain is confined tothe pretubular aggregate and early-stage epithelia derived

WNT-off state

Plasmamembrane

Plasmamembrane

FZD

WNT

FZDDVL

DVL

Degradationcomplex

Axin

Axin

APC

APC

WTX

WTXUbiquitin

P

TLE/Groucho

HDAC Repression Transcription

TCF/Lef1 TCF/Lef1

Target gene Target gene

NucleusNucleus

P P PPP

Proteasome

Proteasome

β-Catenin

β-Catenin

β-Cateninβ-Catenin

β-Catenin

β-Catenin

GSK3β

GSK3β

LRP LRP

WNT-on state

Figure 1 | Canonical WNT signaling. WNT—off state: In the absence of WNT ligands a b-catenin degradation complex (containingaxin, APC (adenomatous polyposis coli), WTX, and GSK3b) promotes N-terminal phosphorylation of b-catenin. This leads toubiquitin-mediated proteasomal degradation of b-catenin and keeps intracellular levels low. Meanwhile, TCF/Lef1 type transcription factorsrecruit TLE/Groucho and histone deacetylases (HDAC) to repress WNT target genes. WNT—on state: Once WNT ligands bind to FZD(Frizzled)/LRP (lipoprotein receptor-related protein) co-receptors, the b-catenin degradation complex is inhibited through recruitment of itscomponents to the FZD/LRP/DVL (Dishevelled) complex. Consequently, b-catenin accumulates intracellularly, translocates to thenucleus, and displaces TLE/Groucho from TCF/Lef1. This interaction promotes the transcription of WNT target genes.

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subsequently. Similar to Wnt9b mutants, Wnt4 gene-deletedmouse embryos display pronounced kidney hypoplasia and anear-complete arrest of tubulogenesis at the stage of thepretubular aggregate with only few progenitor cells convert-ing into more advanced stages of nephron formation.6,17

Remarkably, a loss-of-function WNT4 mutation has recentlybeen implicated in a severe renal hypoplasia syndrome inhumans, indicating that this molecule has a conserved role inmammalian kidney development.18 More generally, thisobservation is the first piece of evidence supporting thenotion that defective WNT signaling in epithelial progenitorsparticipates in human congenital diseases of the kidney.

When metanephric mesenchymes from mouse or ratembryos are isolated from the ureteric bud and placed inorgan culture, they undergo rapid apoptosis and fail toconvert into epithelia unless they are recombined with eitherthe ureteric bud or surrogate stimuli. Remarkably, WNTligands (including Wnt4 and Wnt9b), when expressed fromco-cultured fibroblasts placed adjacent to the metanephricmesenchyme provide such surrogate stimuli. As a result, themesenchyme survives and undergoes complete conversioninto nephron-like epithelia in their presence.5,7,19 Indeed,these data suggest that Wnt9b fulfills the criteria of theureteric bud-derived metanephric mesenchyme inducer thatwas proposed over half a century ago.20 Yet, a note of cautionshould be made when interpreting the available data. First,the epithelial progenitors in the metanephric mesenchymeremain viable and detectable in Wnt9b mutant mice, asdetermined by Pax2 and Gdnf staining.7 This state of affairscontrasts to what is observed in organ culture after removalof the ureteric bud. This finding suggests that additionalfactors emanating from the ureteric bud ensure survival ofthese progenitors. Also, the data obtained by use of WNT-expressing fibroblasts as a source of the WNT ligands leavesopen questions. For instance, to elicit their anti-apoptoticand differentiation-inducing activity WNT ligands must beexpressed from co-cultured fibroblasts that are in directcontact with the isolated metanephric mesenchymal pro-genitors.5 Supernatants from WNT-expressing cells alone areineffective as are recombinant WNT proteins.21 Furthermore,the type of cell line used for WNT protein expression in co-culture experiments appears to affect the outcome.7 Theseobservations suggest that WNT ligands may require addi-tional co-factors to elicit their full survival and differentia-tion-inducing activity. Direct overexpression of WNT ligandsin the isolated metanephric mesenchyme in a feeder-freesystem may resolve these issues, but has not been attempted.Despite these reservations, WNT ligands clearly constitutecentral players in the course of nephron development.

THE ROLE OF b-CATENIN/TCF/LEF1 SIGNALING IN NEPHRONINDUCTION AND EPITHELIAL DIFFERENTIATION

Is b-catenin/TCF/Lef1 signaling necessary for WNT-depen-dent effects in the metanephric mesenchyme? Conditionalb-catenin gene deletion in the metanephric mesenchyme inmice leads to marked renal hypoplasia and a reduction in

several direct or indirect target genes, including Pax8, Wnt4,Fgf8, and Lhx1. 22 Nephron numbers are markedly reduced inthese mutant kidneys and the few nascent nephrons observedin these animals may form as a result of incomplete b-cateningene deletion.22 Overall, the phenotype of metanephricmesenchymal b-catenin mutants resembles that of Wnt9bmutants suggesting an involvement of b-catenin downstreamof Wnt9b. Is this effect mediated by TCF/Lef1 transcriptionfactors? Although direct in vivo data are missing, ratmetanephric mesenchymal cells induced to express adominant-negative N-terminal truncation mutant of TCFundergo apoptosis and are progressively depleted in theorgan culture model of metanephric mesenchymal differ-entiation.9 Taken together, these data suggest a model inwhich a WNT/b-catenin/TCF/Lef1 signaling axis in themetanephric mesenchyme is required for the formation ofthe pretubular aggregate and thus a prerequisite for nephrondevelopment.

Is b-catenin/TCF/Lef1 signaling sufficient to triggerepithelial conversion from metanephric mesenchymal pro-genitors? Lithium chloride and bromoindirubin-30-oxime,both GSK3b inhibitors, are each sufficient to prevent apop-tosis and induce the appearance of nephron-like epitheliaexpressing polarity markers such as E-cadherin when appliedto isolated metanephric mesenchyme. The inhibitors appearto ‘phenocopy’ the effect of WNT-expressing cell lines andother surrogate inducers.9,23,24 This effect is associated withincreased levels of cytoplasmic b-catenin and the inductionof two putative b-catenin/TCF/Lef1 target genes in themetanephric mesenchyme, namely Tcf7 (often referred to asTcf-1) and Lef1.23 These data suggest that WNT-inducedGSK3b inhibition may be a key mechanism in nephrondifferentiation and that stabilization of b-catenin may beinvolved in this activity. In addition, combinations of non-WNT growth factors, including either leukemia inhibitoryfactor or transforming growth factor-b2, are sufficient toactivate nephron differentiation in isolated rat metanephricmesenchyme, which is accompanied by binding of TCF/Lef1consensus oligos by nuclear extracts of these progenitors.8

Furthermore, leukemia inhibitory factor activates a setof direct b-catenin/TCF/Lef1 target genes in rat metanephricmesenchyme, including Pax8, Emx2, and Ccnd1, which maybe secondary to a leukemia inhibitory factor-inducedupregulation of Wnt4 expression.9 These data suggest thatWNT/b-catenin/TCF/Lef1 signaling may be a commonpathway activated by all nephron-inducing growth factorsthus far identified.

However, WNT ligands, inhibitors of GSK3b, and induc-tive growth factors may trigger important intracellular eventsin epithelial progenitors other than the stabilization ofb-catenin. Importantly, the WNT/GSK3b axis has recentlybeen shown to activate intracellular signaling independentof b-catenin stabilization.25 To differentiate b-catenin-dependent from b-catenin-independent effects, geneticallystabilized b-catenin mutants are used to facilitate a pureactivation of the b-catenin pathway and to omit effects on

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other GSK3b targets.26 Interestingly, the conditionalb-catenin stabilization in metanephric mesenchymal epithe-lial progenitor cells in vivo leads to the formation of ectopiccell aggregates that express markers of the pretubularaggregate, including Pax8, Wnt4, Fgf8, and Lhx1.22 Thiseffect is also observed on a Wnt9b- or Wnt4-deficient geneticbackground.22 The finding suggests that b-catenin stabiliza-tion is a sufficient mechanism by which these WNT ligandsinitiate renal epithelial cell lineage progression up to thepretubular aggregate stage. Similarly, when b-catenin isstabilized in the isolated metanephric mesenchyme placedin organ culture, the cells escape apoptosis, proliferate, andinitiate pretubular aggregate marker expression.9,22,23 Re-markably, polarized epithelia are observed in neither setting.In fact, E-cadherin expression is completely absent in the cellaggregates induced by stabilization of b-catenin.9,22 More-over, when b-catenin is stabilized in the metanephricmesenchyme in vivo, the cellular transition to epithelialstructures is completely blocked, even in the presumed presenceof endogenous ureteric bud-derived inductive signals.22 Inaddition, the differentiation-inducing effect of GSK-3b inhibi-tors in the isolated metanephric mesenchyme is only presentwhen these agents are applied transiently or at low dosages,whereas high dosages block differentiation.9,23 Together, thesedata suggest that b-catenin/TCF/Lef1 signaling may in fact beantagonistic to the epithelial conversion of pretubular aggre-gates. This model is consistent with the observation thatb-catenin/TCF/Lef1 signaling inhibits differentiation featuresin cultured epithelial cells from other lineages.27,28

These observations may be relevant not only in the settingof normal renal organogenesis, but also during tumorigen-esis. Notably, stabilization of b-catenin is frequently observedin Wilms tumor, a common pediatric kidney malignancy,which is thought to be initiated in ‘nephrogenic rests’, that is,islands of persistent blastema in the otherwise fully developedkidney.29 Ten to fifteen percent of Wilms tumors displayoncogenic mutations of b-catenin.30 Another one thirdof Wilms tumors are related to inactivating mutations ofthe X-linked tumor suppressor gene WTX,31 which normallyassociates with the b-catenin degradation complex andpromotes b-catenin disposal (Figure 1).32 Blastemal regionsof Wilms tumors express a series of genes also expressedin the metanephric mesenchyme.2,33 Suggesting that theresponse of these cells to an activation of b-catenin/TCF/Lef1signaling may be similar. Thus, in analogy to its effects in themetanephric mesenchyme, b-catenin signaling may contri-bute to the differentiation arrest in Wilms tumors and—at the same time—promote cellular proliferation.

Interestingly, b-catenin/TCF/Lef1 signaling has alsorecently been implicated in ureteric bud epithelial differen-tiation. In contrast to the differentiation of the proximalnephron from mesenchymal progenitors, the ureteric budis formed by budding from a pre-existing epithelial tube,the Wolffian duct. Although all cells of the ureteric budhave already undergone epithelial conversion, the moreimmature distal branches express several genes associated with

branching morphogenesis, such as Ret and Wnt11,34 but lackseveral markers of terminal collecting duct differentiation,namely aquaporin 3 or ZO-1aþ .35 A conditional b-cateningene deletion in the ureteric bud causes premature terminalepithelial differentiation even in the distal-most tips, which isassociated with a defect of ureteric branching morphogenesisand severe renal hypoplasia/dysplasia.35,36 Furthermore,conditional b-catenin stabilization in the ureteric bud anta-gonizes terminal differentiation of collecting duct epithelia.35

These data suggest a more general model, where b-catenin/TCF/Lef1 signaling in the renal epithelial lineage is associatedwith ongoing morphogenesis but inhibitory to terminaldifferentiation.

These bimodal b-catenin signaling effects are consistentwith studies of in vivo TCF/Lef1 signaling activity in micethat express b-galactosidase reporters driven by TCF/Lef1-responsive promoters.9,37,38 Their activity is confined to theimmature regions of the ureteric bud and to early-stagemetanephric mesenchymal-derived epithelia, but becomesundetectable in the more mature portions of the nephron.Whereas all in vivo TCF/Lef1 reporters appear to displaysome context-dependent differences in sensitivity andspecificity,39 this model is also supported by the expressionpatterns of b-catenin/TCF/Lef1 target genes, including Pax8,Emx2, and Ccnd1.9,36

One challenge for future studies will be to morethoroughly elucidate the consequences of this temporal andspatial b-catenin/TCF/Lef1 signaling activity window in thecourse of nephron formation. An intriguing hypothesis isthat the appropriate balance of b-catenin/TCF/Lef1 signalingand non-canonical WNT/PCP signaling is critical forterminal epithelial differentiation, as well as proper tubularelongation and nephron patterning. Defects in epithelialdifferentiation in nephron progenitors that express stabilizedb-catenin may possibly be related to a disrupted balance ofthe two WNT signal transduction branches. This idea issupported by experiments carried out in a recently developedcolony-forming assay system of clonally isolated metanephricmesenchymal progenitors that are co-cultured with Wnt4-expressing fibroblasts.21 In these progenitors, inhibition ofJun N-terminal kinase, a late step in PCP signaling, impairsE-cadherin-positive epithelial cell differentiation suggesting arequirement of PCP signaling for terminal epithelialdifferentiation. Furthermore, in epithelia that have completedterminal differentiation, constitutive b-catenin signalingactivation by conditional adenomatous polyposis coli in-activation or overexpression of stabilized b-catenin promotesthe development of epithelial cysts. These cysts displaycharacteristic apical–basal polarity defects, which may beindicative of a differentiation defect.40,41 Consistently, severalmolecules that inhibit cystogenesis, including the ciliaryproteins inversin, Bbs4, and Kif3a, have since been identifiedas negative b-catenin/TCF/Lef1 signaling regulators.42–44 Inthe case of inversin and Bbs4, a reciprocal modulation of PCPsignaling has been demonstrated.42,43 These data point to anintricately coordinated molecular machinery in developing

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and mature renal epithelia that controls the balance of thetwo WNT signaling branches. However, a more directcharacterization of PCP signaling and b-catenin/TCF/Lef1signaling and their interaction is warranted to definitivelyestablish their individual contributions.

Although many open questions remain, the fact thatWNT/b-catenin signaling is a necessary and sufficient triggerof the early stages of nephron differentiation is now clear. Theperspectives for the future will be threefold: (1) to delineatethe role of b-catenin at later stages of epithelial development;(2) to elucidate the detailed roles of additional WNT/GSK3b-dependent and non-canonical WNT pathways; and, (3) todissect WNT-dependent from WNT-independent mecha-nisms by additional methods.

DISCLOSUREAll the authors declared no competing interests.

ACKNOWLEDGMENTSWe are grateful to Friedrich C. Luft for the insightful commentsconcerning the manuscript. Kai M. Schmidt-Ott is an Emmy NoetherFellow of the Deutsche Forschungsgemeinschaft, Germany (SCHM1730/2-1). Jonathan Barasch is supported by grants from the Marchof Dimes, the Emerald Foundation, and the National Institute ofDiabetes and Digestive and Kidney Diseases (Grants DK-55388 andDK-58872).

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