1 Developmental Genetics, Dept. of Clinical-Biological Sciences (DKBW),
University of Basel Medical School, c/o Anatomy Institute, Pestalozzistrasse
20, CH-4056 Basel, Switzerland
2 Department of Developmental Biology, Utrecht University, Padualaan 8,
NL-3584CH Utrecht, The Netherlands
3 Transgenic Service, EMBL, Meyerhofstrasse 1, D-69117 Heidelberg, Germany
4 Department of Histology, Anatomy Institute, Pestalozzistrasse 20, CH-4056
Basel, Switzerland
Author for correspondence (e-mail:
aimee.zuniga{at}unibas.ch)
Accepted 5 May 2004
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SUMMARY |
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Key words: BMP antagonism, Grem1, Gremlin, Kidney, Limb bud, Mouse, Organogenesis
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Introduction |
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In addition to the limb bud, Grem1 is expressed by a variety of
embryonic structures including lung (Lu et
al., 2001; Shi et al.,
2001
) and kidney rudiments (this study). Development of the
definitive metanephric kidney is initiated by formation and growth of the
ureteric bud. As the ureteric bud invades the metanephric mesenchyme, it
induces condensation and nephrogenesis through reciprocal interactions
(Saxén, 1987
). Genetic
analysis in the mouse shows that the Wt1 and Pax2
transcription factors (Kreidberg et al.,
1993
; Torres et al.,
1995
) control the induction of metanephric development. By
contrast, the extracellular signals that trigger ureteric bud formation in the
posterior part of the Wolffian duct and initiate ureter growth and branching
have so far remained largely elusive. The tips of the invading ureter express
the tyrosine kinase receptor RET (Pachnis
et al., 1993
; Towers et al.,
1998
), whereas RET ligand GNDF is expressed in the condensing
metanephric mesenchyme (Hellmich et al.,
1996
; Towers et al.,
1998
). Genetic analysis has established that the
epithelial-mesenchymal signaling interactions mediated by RET and GNDF are
essential for metanephric development
(Vainio and Lin, 2002
). BMP
signaling has also been implicated in metanephric development as potential
regulator of ureter growth, branching and nephrogenesis
(Dudley et al., 1995
;
Luo et al., 1995
;
Martinez and Bertram, 2003
;
Miyazaki et al., 2000
;
Raatikainen-Ahokas et al.,
2000
). In particular Bmp4, which is expressed by the
mesenchyme surrounding the Wolffian duct and ureter stalk seems to fulfill a
dual function during early metanephric development. Heterozygous Bmp4
mutant mouse embryos display a variable kidney phenotype characterized by
defects in ureteric epithelium growth and induction of ectopic ureter
branching (Miyazaki et al.,
2000
; Raatikainen-Ahokas et
al., 2000
). These studies have also provided evidence that BMP
signaling regulates ureteric bud initiation and branching. An involvement of
BMP antagonism has been postulated, but the relevant antagonist(s) remained to
be identified (Miyazaki et al.,
2000
). To study the essential functions of the BMP antagonist
Grem1, we have deleted the Grem1 open reading frame (ORF) by
homologous recombination in mouse embryonic stem (ES) cells. We report that
Grem1-deficient mice die shortly after birth because of disruption of
kidney and lung organogenesis. During limb bud development, Grem1 is
required for survival of core mesenchymal cells and to establish a functional
AER expressing different types of signals, which regulate Shh
expression and progression of limb bud morphogenesis. During kidney
organogenesis, Grem1 is required to initiate ureter growth and
branching that in turn induces metanephric nephrogenesis. Together, these
results reveal a common and essential role of Grem1-mediated BMP
antagonism in initiating dynamic epithelial-mesenchymal signaling.
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Materials and methods |
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In vitro grafting and culturing of mouse limb buds (trunk cultures)
Mouse forelimb buds were cultured and grafted as described
(Zuniga et al., 1999) with the
following modifications. Trunks with attached forelimb buds were isolated from
either wild type, heterozygous or Grem1-deficient embryos. Embryos
were staged by counting somites and genotyped by PCR. Spherical cell
aggregates were grafted into the forelimb buds and trunks and were cultured
for 15 hours in serum-free medium in 6.5% CO2 at 37°C. The
culture medium was prepared by supplementing high glucose DMEM (GIBCO BRL)
medium, with L-glutamine, penicillin/streptomycin, non-essential amino acids,
sodium pyruvate, D-glucose, L-ascorbic acid, lactic acid, d-biotin, vitamin
B12 and PABA. QT6 fibroblast cells expressing Shh and Grem1
under control of the CMV promoter were prepared using standard calcium
phosphate transfection (Zuniga et al.,
1999
). One day after transfection, spherical cell aggregates were
prepared by plating cells at high density on bacterial plates. The following
day, cells were treated with mitomycin C for 1 hour to block proliferation.
After washing the cell aggregates extensively, they were grafted into
recipient limb buds (a detailed protocol for media preparation, limb bud
grafting and culturing is available upon request).
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Results |
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The limb phenotypes observed in Grem1-deficient mice correspond to a strong and fully penetrant ld limb phenotype (Fig. 2G-J). The zeugopods of Grem1-deficient newborn mice are differentially affected as ulna and radius fuse during onset of ossification, while only one skeletal element forms in hind limbs (arrows, Fig. 2G-J). The autopods are severely truncated because of metacarpal fusions (arrowheads, Fig. 2H,J), reductions in digit numbers and loss of posterior identities together with soft tissue webbing (Fig. 2H,J; data not shown).
Mesenchymal Gremlin 1-mediated BMP antagonism is required for proper AER formation and epithelial-mesenchymal signaling in limb buds
During limb bud morphogenesis, the number of Shh-expressing cells
and transcript levels increase progressively in wild-type embryos
(Fig. 3A)
(Riddle et al., 1993). By
contrast, the Shh expression domain remains small and levels stay low
in limb buds of Gre
ORF homozygous embryos
(Fig. 3A; data not shown). This
failure to propagate SHH signaling has been attributed to the disruption of
the SHH/FGF4 feedback loop (Haramis et
al., 1995
; Khokha et al.,
2003
; Zuniga et al.,
1999
). However, analysis of Gre
ORF
homozygous embryos reveals a general disruption of AER morphology and function
(Figs 3,
4). Activation of Fgf8
in the limb bud ectoderm and thereby initiation of AER formation occur
normally in Grem1-deficient limb buds
(Fig. 3B, E9.5). However, the
Fgf8-expressing AER cells remain more spread out along the
dorsoventral ectoderm, revealing the early disruption of AER morphology in
Grem1-deficient limb buds (Fig.
3B, E9.75). As development proceeds, Fgf8-expressing
cells become restricted to the apex, but the domain remains patchy in mutant
limb buds (Fig. 5E,G; data not
shown), owing to the defects in AER morphology
(Fig. 4E,F). In addition, FGF
signaling by the posterior AER (Martin,
1998
) is completely disrupted as neither Fgf4 nor
Fgf9 nor Fgf17 is activated in Grem1-deficient limb
buds (Fig. 3C and data not
shown).
|
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Particularly Bmp2 has been considered a direct transcriptional
target of SHH signaling in the mesenchyme
(Drossopoulou et al., 2000).
Therefore, reduced Bmp2 expression could be a consequence of reduced
SHH signaling and thus secondary to disrupting Grem1. However,
posterior grafts of Shh-expressing fibroblasts, which are capable of
rescuing gene expression (Zuniga et al.,
1999
), fail to upregulate Bmp2 expression in limb buds of
Gre
ORF homozygous embryos
(Fig. 5A,B). By contrast,
grafts of Grem1-expressing fibroblasts enhance mesenchymal
Bmp2 transcription and restore Bmp2 expression in the AER of
mutant limb buds (Fig. 5C,D).
Similarly, Grem1 (Fig.
5G,H) but not Shh grafts
(Fig. 5E,F) restore Fgf8,
Fgf4 (Zuniga et al.,
1999
) and Fgf9 (data not shown) expression in the AER of
mutant limb buds. These results establish that mesenchymal Grem1
modulates Bmp2 and Fgf8 expression positively and is
required for activation of FGF genes in the posterior AER.
Gremlin 1 is essential for metanephric kidney organogenesis
The bilateral renal agenesis in GreORF
homozygous newborn mice in the context of an otherwise normal urogenital
system (Fig. 2B) indicates an
unexpected essential role of Grem1 during metanephric kidney
organogenesis. Metanephric kidney development is initiated by invasion and
induction of the metanephric mesenchyme by the ureter between embryonic days
10.5 to 11.0 in mouse embryos (Vainio and
Lin, 2002
). Grem1 is initially expressed by the
intermediate mesenchyme (Pearce et al.,
1999
) and from about embryonic day 9.5 onwards by the Wolffian
duct and mesonephric tubules (Fig.
6A and data not shown). During onset of metanephric development,
Grem1 is rapidly downregulated and restricted posteriorly in the
Wolffian duct (Fig. 6B; data
not shown). At this stage, Grem1 is expressed locally in the
condensing metanephric mesenchyme, which surrounds the ureteric bud
(Fig. 6C). The Pax2
transcription factor is essential for urogenital development and acts upstream
of the signal(s) initiating metanephric development
(Torres et al., 1995
). During
ureteric bud formation, Pax2 expression is not affected in
Gre
ORF homozygous embryos (data not shown). By
contrast, invasion of the metanephric mesenchyme by the ureter and
upregulation of Pax2 expression in the induced mesenchyme fail to
occur in Grem1 deficient embryos
(Fig. 6D). The failure to
induce metanephric development becomes more apparent as development
progresses. Pax2 expression is lost from the mutant metanephric
mesenchyme by embryonic day 12.5, while nephrogenesis progresses in wild-type
embryos (Fig. 6E). In addition,
Bmp2, Bmp7 (Fig. 6F,G)
and Wnt4 transcripts (data not shown) are absent from the mutant
metanephric mesenchyme. These results are indicative of a possible failure to
induce condensation of the metanephric mesenchyme.
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Discussion |
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The present study establishes that Grem1-mediated antagonism of
BMP signaling is required for proper AER formation and function. However in
Grem1-deficient limb buds, the expression of genes controlling
dorsoventral axis formation is normal (A.Z., unpublished) and both the AER and
Fgf8 expression are induced indistinguishable form wild-type limb
buds (this study). The AER and Fgf8 expression are induced by
Wnt3/ß-catenin and BMP signaling activities in the
ectoderm during initiation of limb bud development and establishment of
dorsoventral polarity (Barrow et al.,
2003; Kawakami et al.,
2001
; Pizette et al.,
2001
; Soshnikova et al.,
2003
). Grem1 functions subsequently by antagonizing BMP
signaling in the distal limb bud mesenchyme, which is obviously essential for
progression of AER formation and establishment of multi-factorial AER
signaling. In Grem1-deficient limb buds, enhanced mesenchymal BMP
signaling blocks AER maturation and signaling at an early stage and disrupts
distal limb bud morphogenesis, last but not least through apoptosis of core
mesenchymal cells (see also below). These results corroborate previous studies
in chicken embryos, which showed that mesenchymal BMP antagonism maintains the
AER and promotes distal limb bud morphogenesis
(Capdevila et al., 1999
;
Pizette and Niswander,
1999
).
Furthermore, Grem1-mediated BMP antagonism has been implicated in
regulating Shh expression through its role in establishment of the
SHH/FGF4 feedback loop (Capdevila et al.,
1999; Zuniga et al.,
1999
; Khokha et al.,
2003
). During initiation of limb bud development, Shh
expression is activated in the posterior mesenchyme under the influence of
FGF8 signaling by the AER, probably in combination with FGF4
(Lewandoski et al., 2000
;
Moon and Capecchi, 2000
;
Sun et al., 2002
). In
particular, Shh is not activated in hindlimb buds lacking both
Fgf8 and Fgf4, despite continued expression of
Grem1 in the mesenchyme and Fgf9, Fgf17 and BMP genes in the
mutant AER (Sun et al., 2002
).
These results together with our studies
(Zuniga et al., 1999
) also
show that Grem1 functions initially independent of SHH in AER
formation and FGF gene activation in the posterior AER. During progression of
limb bud morphogenesis, Grem1 induced FGF signaling by the posterior
AER participates in dynamic SHH regulation as Grem1 rescues
Shh expression with kinetics similar to FGF4 in ld mutant
limb buds (L.P., unpublished). The general disruption of AER-FGF signaling
underlies the failure to upregulate Shh signaling in
Grem1-deficient limb buds. Through establishment of feedback
signaling, Grem1 mediates the dynamic regulation of both limb bud
signaling centers. For example, the distal-anterior progression of mesenchymal
Grem1 expression during limb bud morphogenesis causes anterior
expansion of FGF signaling in the AER, which in turn regulates SHH signaling
by the polarizing region (Zuniga et al.,
1999
). These dynamic changes alter the ratios of different peptide
signals received by both AER cells and the underlying limb bud mesenchyme.
Sanz-Ezquerro and Tickle (Sanz-Ezquerro
and Tickle, 2000
) have shown that the size and signaling strength
of the Shh expression domain in limb buds is tightly regulated by
apoptosis. Taken together, the analysis of epithelial-mesenchymal signaling in
limb buds indicates that Shh expression is not regulated by a mere
SHH/FGF feedback loop, but through complex and dynamic feedback signaling
involving different types of mesenchyme and AER signals, and their antagonists
belonging to the FGF, BMP and WNT gene families.
In Grem1-deficient mouse limb buds, prominent apoptotic cell death
is observed in the core mesenchyme from about embryonic day 11.0 onwards. This
cell death pattern is rather distinct from the ones observed in Shh
deficient (te Welscher et al.,
2002) and Fgf4/Fgf8 double mutant
(Sun et al., 2002
) mouse
embryos and following AER removal (Dudley
et al., 2002
). In addition, experiments in chicken embryos have
provided evidence for a role of Grem1-mediated BMP antagonism in cell
survival during digit formation and chondrogenesis
(Merino et al., 1999
). During
the onset of chondrogenesis, Grem1 acts in a paracrine fashion on the
adjacent (core-) mesenchyme to protect it from undergoing programmed cell
death (this study). Therefore, this anti-apoptotic function of Grem1
could provide an explanation for the reductions and fusions of distal limb
skeletal elements observed in Grem1-deficient mouse embryos. It is
possible that the effect of Grem1-mediated BMP antagonism on cell
survival is direct and does not involve feedback signaling between mesenchyme
and AER.
The complete renal agenesis in Grem1-deficient mice reveals that
the BMP antagonist Grem1 is required for metanephric development.
This study identifies Grem1 as the essential extracellular signal,
which initiates metanephric kidney development by enabling the ureter to
invade the metanephric mesenchyme. However, establishment of the two signaling
centers controlling metanephric development, the ureteric bud (expressing RET)
and metanephric mesenchyme (expressing GDNF), occurs without Grem1;
while initiation of the ureter growth and branching depend on Grem1
function. In analogy to its function in limb buds, Grem1 regulates
the transition to dynamic signaling interactions to enable induction of
metanephric organogenesis. During set-up of RET/GDNF signaling and ureteric
bud formation, Grem1 is expressed by the Wolffian duct and locally by
the metanephric mesenchyme, but the primary tissue affected in
Grem1-deficient embryos could be the ureteric epithelium as is the
case in ld homozygous embryos
(Maas et al., 1994). Such
impairment of epithelium to mesenchyme signaling disrupts upregulation of
Gdnf, Pax2 and Ret expression in the mesenchyme and tips of
the invading ureter, respectively. This disruption in turn leads to complete
elimination of the metanephric mesenchyme by apoptotic cell death. This
phenotype is strikingly similar to the one caused by inactivation of
Sall1, a transcription factor expressed by the metanephric mesenchyme
(Nishinakamura et al., 2001
).
However, Sall1 remains expressed in Grem1 mutant embryos
(O.M. and A.Z., unpublished), which indicates that it is not a direct
target.
Several BMP genes are expressed during initiation of metanephric kidney
development and have been implicated in the early inductive events
(Martinez and Bertram, 2003;
Vainio and Lin, 2002
). In
particular, analysis of Bmp4 heterozygous embryos has provided
evidence for its essential roles during ureter morphogenesis
(Miyazaki et al., 2000
;
Raatikainen-Ahokas et al.,
2000
). BMP4 (possibly similar to BMP2)
(Gupta et al., 1999
) inhibits
ectopic branching of the ureteric bud and is required for growth of the ureter
stalk. These studies (Miyazaki et al.,
2000
; Raatikainen-Ahokas et
al., 2000
), together with ours, reveal the likely mechanism by
which metanephric development is initiated. Ureteric bud formation by the
Wolffian duct is independent of Grem1-mediated BMP antagonism, while
it is required to induce ureter growth, branching and propagation of RET/GDNF
feedback signaling. During branching morphogenesis, Grem1 is
expressed locally in the mesenchyme surrounding the invading ureter (this
study) and Bmp4 in mesenchyme adjacent to the ureter stalk
(Dudley and Robertson, 1997
;
Miyazaki et al., 2000
).
Dynamic local changes in BMP activity as mediated by antagonistic
Grem1-BMP2/4 interactions may regulate the temporal and spatial
kinetics of ureter branching, while BMP signaling alone promotes ureter stalk
elongation (Miyazaki et al.,
2000
; Raatikainen-Ahokas et
al., 2000
). Grem1-mediated BMP4 antagonism has also been
implicated in branching morphogenesis and proximodistal patterning of
embryonic lungs (Lu et al.,
2001
; Shi et al.,
2001
). Consistent with these results, airway epithelia are
defective in lungs of Grem1-deficient newborn mice (this study). In
summary, the present study reveals that Grem1-mediated BMP antagonism
regulates the dynamic interactions of diverse epithelial and mesenchymal
signaling centers during progression of vertebrate organogenesis.
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ACKNOWLEDGMENTS |
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Footnotes |
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