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First published online 30 May 2007
doi: 10.1242/dev.006155
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Department of Molecular and Cellular Biology, Harvard University, 16 Divinity Avenue, Cambridge, MA 02138, USA.
Author for correspondence (e-mail:
amcmahon{at}mcb.harvard.edu)
Accepted 16 April 2007
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SUMMARY |
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 TOP SUMMARY INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key words: Canonical Wnt signaling, Nephrogenesis, Mesenchymal-to-epithelial transition, Tubulogenesis, Mouse
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INTRODUCTION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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;
Yu et al., 2004). Reciprocal
and repetitive inductive interactions between the invading ureteric bud and
adjacent metanephric mesenchyme results in branching growth of the ureteric
bud, elaborating the network of the collecting duct system for urine transport
and induction of a mesenchymal-to-epithelial transition within the mesenchyme,
establishing the renal vesicles, the precursors of the renal tubule
(Mori et al., 2003;
Vainio and Lin, 2002;
Yu et al., 2004). Renal
vesicle formation is preceded by the appearance of pre-tubular aggregates of
induced mesenchyme beneath the tip of the branching ureteric epithelium.
There, aggregates then transition to epithelial renal vesicles over a period
of several hours. Subsequently, the renal vesicle undergoes extensive growth
and complex morphogenesis and patterning that result in the establishment of
mature nephrons (Mori et al.,
2003; Vainio and Lin,
2002; Vize et al.,
2003; Yu et al.,
2004).
Two members of the Wnt family of lipid-modified secreted glycoproteins,
Wnt9b and Wnt4, play central roles in the initial stages of the tubulogenic
program (Carroll et al., 2005;
Kispert et al., 1998;
Stark et al., 1994).
Wnt9b is expressed in the ureteric epithelium, whereas Wnt4
is expressed in the pre-tubular aggregate, as one of the first molecular
responses to inductive signaling mediated by the ureteric epithelium. Genetic
analyses of Wnt9b and Wnt4 mutant mice indicate that
Wnt9b is a primary inductive signal required for all aspects of renal
vesicle induction, including the activation of Wnt4
(Carroll et al., 2005). Wnt4
appears to play an auto-inductive role within the induced mesenchyme; one that
is essential for propagating the inductive process and completing the
transition to epithelial renal vesicles
(Kispert et al., 1998;
Stark et al., 1994). Although
the importance of these signals is clear, the molecular pathways through which
these sequential signals operate have not been determined.
Wnts can activate several pathways (reviewed by
Clevers, 2006;
Nelson and Nusse, 2004). The
best defined has been termed the canonical Wnt pathway. In this, Wnt-mediated
signaling counters a phosphorylation-triggered pathway of proteosomal
degradation, thereby enabling the stabilization of ß-catenin in receiving
cells. Elevated levels of ß-catenin allow the formation of complexes
between ß-catenin and TCF/LEF DNA-binding proteins. The resulting
activator complex directly regulates transcriptional targets
(Nelson and Nusse, 2004). Wnt
signaling has also been shown to regulate cell polarity and cell movement, at
least in part through the JNK signaling pathway, to increase the intracellular
concentration of calcium in various contexts, and through a PKA/CREB-based
mechanism in muscle specification (Chen et
al., 2005; Pandur et al.,
2002; Veeman et al.,
2003).
To explore the mechanism of action of Wnt9b and Wnt4, we investigated the potential role of ß-catenin-dependent signaling in renal vesicle induction in the mammalian kidney. Our data provide strong evidence that ß-catenin-dependent canonical Wnt signaling is the primary mode of both Wnt9b and Wnt4 signaling. Further, our findings suggest that ß-catenin-mediated canonical signaling acts transiently to induce the mesenchyme, as the downregulation of ß-catenin activity is essential for the transition to the fully epithelial state of the renal vesicle.
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MATERIALS AND METHODS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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),
Catnbex3/ex3 (Harada et
al., 1999), ß-catenin+/n
(Haegel et al., 1995),
Wnt4+/n (Stark et al.,
1994) and Wnt9b+/n
(Carroll et al., 2005) mouse
lines have been described previously. The Six2TGC mouse line will be
described more fully elsewhere.
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Explant culture
Metanephric mensenchyme was dissected from E11.5 kidneys as previously
described (Carroll et al.,
2005). Each explant was cultured on Nucleopore Track-Etch Membrane
(pore size=1 µm, Whatman, Florham Park, NJ) in DMEM/10% FBS for 24
hours.
In situ hybridization
E12.5 kidneys and explant culture samples were fixed in 4% paraformaldehyde
at 4°C overnight and dehydrated in methanol. Hybridized samples were
developed in BM purple (Roche, Indianapolis, IN), stored in 80% glycerol and
photographed using a Nikon DXM1200 digital camera.
Immunohistochemistry
Embryonic day 13.5 and 15.5 embryos were fixed in 4% paraformaldehyde at
4°C for 1 hour, incubated in 20% sucrose at 4°C overnight and imbedded
in OCT. Sections (10 µm) were incubated with primary antibodies to
ß-catenin (Epitomics, Burlingame, CA), E-cadherin (Zymed, S. San
Francisco, CA), ß-galactosidase (Cappel, Cochranville, PA) and
Dolichos biflorus DBA lectin (Sigma, St Louis, MO), and secondary
antibodies conjugated to Cy2, Cy3 and Cy5. Sections were photographed on a
Zeiss LSM510 Axioplan inverted confocal microscope.
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RESULTS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Cell fate analysis with this line revealed that
Six2GFP::Cre-positive cells give rise exclusively to renal vesicle derivatives
in the mature kidney. Thus, the Six2GFP::Cre transgene enables
specific modulation of gene activity directly within the renal vesicle
progenitor cell compartment before normal induction.
To examine the role of canonical Wnt signaling in the initiation of
nephrogenesis, we removed ß-catenin activity from the renal vesicle
progenitor component of the metanephric mesenchyme using the Six2TGC
line in combination with a conditional loss-of-function (LOF) allele of
ß-catenin, Catnbc
(Brault et al., 2001;
Harada et al., 1999)
(Catnb is also known as Ctnnb1 - Mouse Genome Informatics).
ß-catenin LOF mutants (Catnbc/-; Six2TGC) reached
term but died within 24 hours of birth. Dissection of newborn mutants revealed
a greatly reduced kidney structure when compared with genetic control
littermates that where phenotypically normal
(Fig. 1A, compare to adrenal
gland). In contrast to wild type, Catnbc/- and
Six2TGC controls (Fig.
1B-D), ß-catenin LOF mutants exhibited few mature nephron
structures and entirely lacked an active nephrogenic zone
(Fig. 1E). The presence of some
epithelial structures with histologically identifiable renal tubule components
(e.g. glomerulus, proximal convoluted tubule) indicated that some
nephrogenesis did occur, although the number of nephrons was greatly reduced
and their organization was abnormal. The absence of normal kidney architecture
most likely accounts for the early postnatal lethality of mutants. Further
histological examination of E13.5 mutant kidneys revealed that nephrogenesis
was dramatically reduced at this early stage
(Fig. 1F,G). In wild-type
kidneys, nephrogenesis was active within the nephrogenic zone of the cortical
region and several renal vesicles and S-shaped bodies could be observed
ventral to the ureteric tips of the collecting duct
(Fig. 1F). By contrast,
ß-catenin LOF mutants lacked a well-defined nephrogenic zone and few
S-shaped bodies were apparent (Fig.
1G). As a secondary consequence of loss of the nephrogenic zone,
ureteric branching was also greatly reduced
(Fig. 2A,B). Together, these
results demonstrate that ß-catenin function is essential for normal
nephrogenesis within the nephron-forming lineage of the mouse kidney.
We next assessed the molecular phenotype resulting from ß-catenin LOF
mutation. Several key genes have been described that demarcate the earliest
molecular responses to inductive signaling within the metanephric mesenchyme
and highlight the transition of responding cells to pre-tubular aggregates and
renal vesicles. Furthermore, functional studies have defined roles for several
of these in the tubulogenic program. Fgf8, Pax8, Wnt4 and
Lhx1 are all expressed within the pre-tubular aggregate; each is also
expressed at later stages in a subset of cells within tubular derivates of the
renal vesicle. Genetic studies have placed Fgf8 and Pax8
upstream of Wnt4 in metanephric mesenchyme induction, although
continued expression of each depends on Wnt4 signaling. Lhx1 lies
genetically downstream of Wnt4
(Kispert et al., 1998;
Kobayashi et al., 2005;
Stark et al., 1994). Loss of
either Fgf8 or Wnt4 signaling results in a complete failure
of the specification of early renal vesicles
(Grieshammer et al., 2005;
Stark et al., 1994). By
contrast, Lhx1 mutants establish a renal vesicle, but the early
morphogenesis and patterning of these is defective
(Kobayashi et al., 2005).
Together, these markers enable a detailed molecular analysis of the initial
steps of the tubulogenic program within induced mesenchyme before formation of
overt epithelial structures.
|
). We also
performed immunohistochemistry using anti-cleaved caspase 3 to address
possible apoptosis of the nephron progenitor pool. We did not observe a marked
increase in apoptosis in ß-catenin LOF compared to controls (data not
shown). This suggests the limited inductive response is not due to apoptosis
of the nephron progenitors. The formation of a reduced number of renal vesicles in the ß-catenin LOF mutant suggests either that ß-catenin is not strictly required for the initiation of tubulogenesis, or that the dynamics of Six2TGC-mediated recombination and/or ß-catenin turnover does not remove all ß-catenin activity before an initial inductive signal. To address this, we examined ß-catenin by immunohistochemistry in E12.5 ß-catenin LOF mutants. Consistent with the latter view, the renal vesicles and S-shaped bodies in LOF mutants retained ß-catenin, suggesting that the earliest forming renal vesicles escaped Cre recombination in our experimental system (see Fig. S1 in the supplementary material). Importantly, no renal vesicles or mature nephron derivatives were observed in the mutants that lacked ß-catenin at this later stage (see Fig. S1 in the supplementary material; data not shown). Collectively, these results are consistent with a cell-autonomous requirement for ß-catenin activity within renal vesicle progenitors for the induction of a tubulogenic program.
Expression of a stabilized form of ß-catenin in the cap mesenchyme initiates tubulogenesis
We further assessed the role of ß-catenin by generating ß-catenin
gain-of-function (GOF) mutants (Catnbex3/+; Six2TGC), in
which a conditional allele of stabilized ß-catenin was expressed within
the metanephric mesenchyme following Six2TGC-mediated excision of the third
exon of ß-catenin. This conditional recombination event generates a
ß-catenin protein lacking degradation target sequences
(Harada et al., 1999); as a
result, ß-catenin accumulates and the canonical pathway is activated in a
ligand-independent process (Harada et al.,
1999).
ß-catenin GOF mutants developed to term but died within 24 hours of birth, exhibiting marked renal agenesis (data not shown). At early stages (E12.5-13.5), ß-catenin GOF mutants showed reduced epithelial branching (Fig. 3A-D) and an absence of epithelial stages of tubulogenesis, although GOF mutant kidneys were slightly larger than control genotypes (Fig. 3A,B). Strikingly, GOF mutants exhibited large clusters of highly condensed mesenchyme beneath the ureteric tips, where pre-tubular aggregates normally form, and variably sized clumps above the ureteric tips in the position, where Six2-positive metanephric mesenchyme is located (Fig. 3A,B).
To assess the progression of tubulogenesis, we examined Wnt4, Fgf8, Pax8 and Lhx1 expression in E12.5 ß-catenin GOF mutants. Control littermates (Catnbex3/+) showed normal expression patterns, as expected for all markers tested (Fig. 3E,G,I,K). By contrast, ß-catenin GOF mutants showed ectopic, disorganized expression of these early markers of the inductive response (Fig. 3F,H,J,L). Both the number and size of Wnt4 and Fgf8 expression domains were dramatically increased in ß-catenin GOF mutants (Fig. 3F,H). Furthermore, ectopic expression of these markers was observed dorsal to the ureteric epithelium in GOF mutants, where uninduced mesenchymal progenitors normally reside (arrows, Fig. 3F,H, and data not shown). Expression of Pax8 and Lhx1 showed a generally similar pattern to that of Fgf8 and Wnt4, although the expression levels of these genes were not markedly elevated (Fig. 3J,L). These data indicate that activation of ß-catenin signaling in the cap mesenchyme population of nephron progenitors is sufficient to initiate an ectopic program of tubule induction. However, the failure to observe overt epithelial structures at later stages suggests that the mesenchymal-to-epithelial transition may be blocked in these cells.
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;
Vize et al., 2003;
Watanabe et al., 1981). In
this, DBA-negative/E-cadherin-positive cells represent epithelial, metanephric
mesenchyme derivatives (e.g. S-shaped body and mature tubules). To identify
ß-catenin GOF cells, a conditional reporter allele (R26R)
(Soriano, 1999) was included
in the crosses so that all cells undergoing Cre-mediated recombination also
expressed ß-galactosidase. In wild-type kidneys,
DBA-negative/E-cadherin-positive cells were ß-galactosidase-positive, as
expected (Fig. 4G). In
ß-catenin GOF mutants, ß-galactosidase-positive cells formed the
large condensates (Fig. 4F).
However, these ß-galactosidase-positive cells were E-cadherin negative
(Fig. 4H), indicating a failure
of epithelial formation when stabilized ß-catenin was continually
present. Thus, whereas stabilization of ß-catenin may be sufficient to
initiate mesenchymal induction, a downregulation or loss of canonical Wnt
activity may be necessary for cellular transition to epithelial
structures.
Activation of ß-catenin in metanephric mesenchyme is sufficient for initiating a tubulogenic program
The ectopic sites of induction following stabilization of ß-catenin
within the metanephric mesenchyme suggest that activation of ß-catenin
may be sufficient for this process. To address this issue, we isolated
metanephric mesenchyme at E11.5 from genetic controls and from embryos that
had undergone Six2TGC-mediated activation of ß-catenin. We then compared
the inductive response in vitro in these mesenchymal explants to that observed
in intact kidney explants. As expected, all markers of mesenchymal induction
were induced in intact explants (Fig.
5A-D) but were absent from isolated control metanephric mesenchyme
explants following 24 hours of culture
(Fig. 5E-H). By contrast, we
observed a robust activation of all markers following ß-catenin
activation in isolated mesenchymal explants, independent of the normal
inductive source, the ureteric epithelium
(Fig. 5I-L).
Activation of early tubule markers by GOF
ß-catenin in cap mesenchyme does not require Wnt4 or Wnt9b
These explant studies raise the question of whether activation of
ß-catenin can functionally replace Wnt signals in the intact kidney in
vivo. As discussed earlier (see Introduction), several studies point to the
sequential action of Wnt signaling in metanephric mesenchyme induction, where
Wnt9b activates Wnt4, Fgf8 and Pax8 in the
pre-tubular aggregate, and Wnt4 is subsequently necessary for
maintaining the expression of these markers and for de novo induction of
Lhx1 (Kobayashi et al.,
2005; Stark et al.,
1994). To determine whether activated ß-catenin could
substitute for the inductive activity of these Wnts, we activated
ß-catenin signaling in Wnt9b null and Wnt4 null mutant
backgrounds (Figs 6 and
7, respectively).
As previously reported, Wnt9b is essential for all molecular readouts of the inductive response and for normal ureteric branching beyond the first bifurcation event that establishes the T-bud stage (Fig. 6A-H). However, activation of stabilized ß-catenin in the cap mesenchyme of Wnt9b mutant at E12.5 was sufficient for mesenchymal induction, reflected by extensive ectopic expression of all these markers (Fig. 6I-P).
At E12.5, Wnt4 mutants and control genotypes expressed
Pax8 and Lhx1 weakly in the ureteric epithelium
(Fig. 7C,D,G,H). However, in
contrast to controls, neither marker was expressed in the mesenchyme of
Wnt4 mutants as expected (Fig.
7G,H). The small foci of Fgf8 expression in Wnt4
mutants (Fig. 7F) was
consistent with evidence that initial Fgf8 activation is independent
of Wnt4 and upstream of Wnt4 itself
(Grieshammer et al., 2005;
Perantoni et al., 2005). When
stabilized ß-catenin was activated in metanephric mesenchyme of
Wnt4 mutants using Six2TGC, we observed ectopic expression
of Fgf8, Pax8 and de novo activation of Lhx1 in the
mesenchyme derivatives (Fig.
7N-P). Together, these results indicate that stabilization of
ß-catenin, the crucial regulatory event in transcriptional regulation of
the canonical Wnt signaling pathway, functionally replaces the activities of
Wnt9b and Wnt4 in induction of metanephric mesenchyme.
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|
DISCUSSION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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;
Kispert et al., 1998;
Stark et al., 1994). Here we
have used genetic approaches to directly manipulate ß-catenin activity
within these progenitors to address the potential role of canonical Wnt
signaling in renal vesicle induction. Several lines of evidence point to a
central role for the canonical Wnt pathway in these inductive events.
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Given the epistatic relationships between Wnt9b and Wnt4, distinguishing
between a model wherein ß-catenin mediates the inductive activity of both
signals versus Wnt4 alone is not straightforward. However, several
observations suggest that canonical Wnt action mediates Wnt9b and Wnt4
inductive responses. First, removal of ß-catenin activity within the
metanephric mesenchyme at E12.5 results in a severe branching deficiency
(Fig. 1G,
Fig. 2B) that is normally
associated with loss of Wnt9b but not Wnt4 signaling. Thus, a Wnt9b-specific
response within the metanephric mesenchyme, mediated through ß-catenin,
may be a component of the reciprocal interaction that coordinates ureteric
epithelial branching with mesenchyme induction. Fgf8 is completely
absent in Wnt9b mutants and present, albeit at reduced levels, in
Wnt4 mutants. Further, Fgf8 signaling has been implicated in the
regulation of epithelial branching in several contexts
(Jaskoll et al., 2004;
Shu et al., 2005). However,
initial branching is not severely defective in Fgf8 mutants
(Grieshammer et al., 2005;
Perantoni et al., 2005); thus
the molecular mediators of this response remain to be determined.
|
);
thus, the restoration of Lhx1 expression indicates a direct role for
ß-catenin-mediated canonical Wnt signaling in the Wnt4 arm of the
inductive response. Although our study suggests that both Wnt4 and Wnt9b act
through ß-catenin in their inductive roles, we cannot rule out the
possibility that they may also activate non-canonical Wnt pathways in
parallel.
|
).
By contrast, branching and expansion of Six2 progenitors continues for an
additional 24 hours or more in the Wnt4 mutant
(Stark et al., 1994). Thus,
the phenotypic differences most likely reflect differences in the number of
Six2 progenitors that exist on each background.
Why do we fail to observe an epithelial transformation on activation of
ß-catenin despite the formation of aggregates and initiation of what
appears to be a normal inductive response? The simplest explanation is that
completion of a mesenchymal-to-epithelial transition requires ß-catenin
signaling to be turned off. In previous studies in which lithium was used as a
non-specific activator of canonical Wnt signaling, high doses blocked tubule
formation (Davies and Garrod,
1995), consistent with our observation here. At present, our
understanding of this crucial cellular event is rudimentary, so we are unable
to directly address how canonical Wnt signaling may specifically inhibit
epithelial formation. However, canonical Wnt signaling could interfere with
other regulatory pathways. For example, several studies indicate that
activation of canonical Wnt signaling can inhibit non-canonical Wnt responses
(Veeman et al., 2003). Thus,
if Wnt4 signaling bifurcates through a canonical (inductive) and a
non-canonical (epithelialization) branch, activated ß-catenin may block
the latter.
The spatial dynamics of mesenchymal induction
Normal renal vesicle induction is first observed within pre-tubular
aggregates beneath the tips of the ureteric bud. Recent evidence has
highlighted the importance of Six2 in regulating spatial induction of
the metanephric mesenchyme (Self et al.,
2006). Six2-expressing cells are restricted to the dorsal
metanephric mesenchyme that caps the ureteric epithelium, and Six2 is
rapidly downregulated in induced pre-tubular aggregates. In the metanephric
mesenchyme, Six2 acts to inhibit a tubulogenic program in renal vesicle
progenitors. Consequently, renal vesicles are formed prematurely and
ectopically on the dorsal side of the ureteric bud in Six2 mutants
(Self et al., 2006). As a
result of the depletion of the progenitor population, kidney development
ceases at an early stage. Our data here indicate that canonical Wnt signaling
within the Six2 population leads to a similar early inductive
response to that observed in Six2 mutants. Thus, within the renal
vesicle progenitor pool, Six2 may act to inhibit canonical Wnt signaling,
which is normally mediated through ureteric epithelial-derived Wnt9b.
Conversely, downregulation of Six2 is one of the earliest indicators
of the induced mesenchyme. Thus, inhibition of Six2 expression
through canonical Wnt signaling may play a central role in modulating Six2
action. While the exact details of the molecular interactions remain to be
determined, our data suggest a crucial regulation of canonical Wnt signaling
within the tip/cap region of the kidney to ensure appropriate local activation
of the inductive response and, importantly, the maintenance of a repopulating
progenitor pool.
In summary, the studies herein further our understanding of the action of Wnt signaling in kidney development, demonstrating that the primary inductive activities of both Wnt9b and Wnt4 are likely to be mediated through canonical Wnt signaling. These findings have mechanistic implications for the maintenance of the progenitor cell compartment and for the mesenchymal-to-epithelial transition that is the cellular readout of these inductive processes.
Supplementary material
Supplementary material for this article is available at
http://dev.biologists.org/cgi/content/full/134/13/2533/DC1
Note added in proof
Kuure et al. have recently presented evidence lending further support to a
linkage between beta-catenin stabilization within the metanephric mesenchyme
and nephron induction (Kuure et al.,
2007).
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ACKNOWLEDGMENTS |
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Footnotes |
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 C.-L. Lin, J.-Y. Wang, J.-Y. Ko, K. Surendran, Y.-T. Huang, Y.-H. Kuo, and F.-S. Wang Superoxide Destabilization of {beta}-Catenin Augments Apoptosis of High-Glucose-Stressed Mesangial Cells Endocrinology, June 1, 2008; 149(6): 2934 - 2942. [Abstract] [Full Text] [PDF]
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 A.-A. Chassot, F. Ranc, E. P. Gregoire, H. L. Roepers-Gajadien, M. M. Taketo, G. Camerino, D. G. de Rooij, A. Schedl, and M.-C. Chaboissier Activation of {beta}-catenin signaling by Rspo1 controls differentiation of the mammalian ovary Hum. Mol. Genet., May 1, 2008; 17(9): 1264 - 1277. [Abstract] [Full Text] [PDF]
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