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First published online 24 November 2005
doi: 10.1242/dev.02175
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1 Department of Molecular Biology and Pharmacology, Washington University School
of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA.
2 Department of Pathology and Immunology, Washington University School of
Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA.
3 The Center for Genome Sciences, Washington University School of Medicine, 660
South Euclid Avenue, St Louis, MO 63110, USA.
* Author for correspondence (e-mail: dornitz{at}wustl.edu)
Accepted 24 October 2005
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SUMMARY |
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 TOP SUMMARY INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key words: Fibroblast growth factor 9 (FGF9), FGF10, Gut development, Cecum, Budding morphogenesis, Epithelial-mesenchymal cross-talk
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INTRODUCTION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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; Roberts,
2000; Snell and Stevens,
1966). At E8, the midgut is first visible as a closed tube
(Kaufman, 1992). Two sac-like
structures, the stomach and cecum, bud from this tube and define functional
subdivisions in the gut. The stomach is positioned at the junction of the
esophagus and the proximal small intestine, whereas the cecum is located at
the junction of the distal small intestine (ileum) and the colon. By E13.5,
the entire gut is lined by a pseudostratified, uniformly proliferative
endoderm (Kaufman, 1992).
The cecum begins to form at E11.5 as a mesenchymal expansion followed by
epithelial budding into the primordial cecal mesenchyme
(Burns et al., 2004). This
process begins prior to the proximal to distal wave of cytodifferentiation
that occurs from E15 to E18 in the small intestinal endoderm, which converts
it to a simple columnar epithelium with rudimentary villi
(Calvert and Pothier, 1990;
Schmidt et al., 1988).
The wall of the cecum, like other parts of the gut tube, contains two types
of tissue: an outer layer of mesoderm-derived mesenchyme and an inner layer of
endoderm-derived epithelium. Developmental studies have demonstrated that an
interaction between the endoderm and mesoderm is required for normal
differentiation of region-specific gut epithelium
(Haffen et al., 1987;
Kedinger et al., 1998;
Koike and Yasugi, 1999;
Roberts et al., 1998).
Reciprocal molecular interactions between epithelium and mesenchyme are
crucial for budding morphogenesis in many organ systems
(Cardoso, 2001;
Shannon and Hyatt, 2004;
Tanaka and Gann, 1995).
Fibroblast growth factors (FGFs) are candidates for cecal development, as
recent studies show that both FGF10 and its receptor, FGFR2b, are required for
the formation of this organ (Burns et al.,
2004).
FGFs bind to and activate four tyrosine kinase receptors (FGFRs) to
regulate intracellular signaling pathways controlling cell proliferation,
differentiation and migration. An alternative splice form of FGFR2 (FGFR2b) is
expressed in epithelial tissues and is activated by mesenchymally expressed
FGFs, such as FGF7 and FGF10. By contrast, FGFR1c and FGFR2c are expressed
primarily in mesenchyme, and are activated by FGF ligands expressed in
epithelia, such as FGF4, FGF8 and FGF9
(Ornitz and Itoh, 2001;
Ornitz et al., 1996). In the
developing lung, FGF9 and FGF10 form a reciprocal pair of ligands that
regulate branching and budding morphogenesis. FGF10 is expressed at high
levels in the distal lung mesenchyme, immediately adjacent to budding airway
epithelium. FGF10 signals through its high affinity receptor, FGFR2b,
resulting in epithelial migration towards the source of FGF10
(Bellusci et al., 1997;
De Moerlooze et al., 2000;
Min et al., 1998;
Sekine et al., 1999). By
contrast, FGF9 is expressed in lung airway epithelium and the mesothelial
visceral pleura, where it regulates lung mesenchymal proliferation.
Fgf9-/- mice have a significant reduction in lung
mesenchyme, and subsequent decreased FGF10 expression, resulting in decreased
lung branching (Colvin et al.,
1999; Colvin et al.,
2001b). Fgf10-/- mice fail to form primary
bronchi and thus have complete agenesis of the lung
(Min et al., 1998;
Sekine et al., 1999). It is
not known whether FGF10 is required for the expression of Fgf9 during
lung branching morphogenesis. Reciprocal FGF signaling also occurs during limb
development. The formation of the limb bud is initiated with the expression of
mesenchymal FGF10, which induces formation of the apical ectodermal ridge
(AER) (Martin, 1998). FGFs 4,
8, 9 and 17 are subsequently expressed in the AER and signal back to limb
mesenchyme.
Although reciprocal FGF signaling pathways have been identified in several
developmental systems, it is not known whether reciprocal FGF signals are
universally required for organogenesis. For example, in midgestational heart
development, FGF9 has been shown to signal from the endocardium and epicardium
to the myocardium. However, a reciprocal myocardial to epicardial signal has
not been identified (Lavine et al.,
2005). We identify FGF9 as a necessary signal to induce expansion
of the cecal mesenchyme. However, FGF9 is not sufficient to induce cecal
development at other sites along the length of the intestine. Moreover,
comparative analysis of both Fgf9-/- and
Fgf10-/- mice demonstrates that expansion of cecal
mesenchyme precedes FGF10 expression and epithelial budding.
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MATERIALS AND METHODS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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;
Min et al., 1998). For embryo
collection, time-mated Fgf9+/- or
Fgf10+/- females were killed at E10.5-E18.5, the embryos
were removed and the intestinal tract was isolated, as previously described
(Stappenbeck and Gordon,
2000). Wild-type or heterozygous littermates from each line were
collected as controls.
Histology and immunohistochemistry
Mouse embryonic GI tracts were fixed overnight in 4% paraformaldehyde
(PFA)/PBS, dehydrated through ethanol, embedded in paraffin, and 5 µm
serial sections were prepared for Hematoxylin and Eosin (H&E) staining and
immunohistochemical staining. To confirm FGFR1 and FGFR2 expression in E12.5
mouse embryonic cecum, the sections were deparaffinized, rehydrated, treated
with blocking solution (Histostain-SP kit, Invitrogen, Carlsbad, CA), and
incubated overnight at 4°C with rabbit anti-FGFR1 and FGFR2 antibodies
(Santa Cruz Biotech, Santa Cruz, CA). The signals were visualized with the
Histostain-SP Kit (Invitrogen, Carlsbad, CA), as recommended by the
manufacturer.
BrdU labeling
For analysis of cell proliferation, time-mated Fgf9+/-
or Fgf10+/- females were given an intraperitoneal
injection of bromodeoxyuridine (BrdU, 120 µg/gm body weight; Sigma) 1 hour
before sacrifice at E12.5-E18.5. The intestinal tract was isolated and
processed for histology. The embedded specimens were cut (5 µm thick
sections), and BrdU-labeled cells were identified by immunohistochemistry
using a monoclonal antibody to BrdU (BD Biosciences). Horseradish
peroxidase-conjugated goat anti-mouse immunoglobulin G was obtained from
BioSource. Bound antibodies were visualized using diaminobenzidine (Sigma) in
the presence of H2O2. Sections were counterstained with
Hematoxylin. Proliferation in the cecal epithelium and mesenchyme was scored
as the ratio of BrdU-labeled nuclei to total cell nuclei in fields viewed
through a 40x objective.
Whole-mount in situ hybridization
Embryonic intestinal tracts were dissected in cold diethyl pyrocarbonate
(DEPC)-treated PBS, fixed overnight in 4% PFA/DEPC-PBS at 4°C, dehydrated
through graded methanol in DEPC-PBT (PBS+0.1% Tween 20) and stored at
-20°C. Whole-mount in situ hybridization was performed as described
(Colvin et al., 2001b).
Control wild-type and Fgf9-/- or
Fgf10-/- tissues were processed together to ensure
identical hybridization conditions. Mouse RNA probes were synthesized from
Fgf9 (Colvin et al.,
1999), Fgf10 (provided by B. Hogan), Shh and
Bmp4 (provided by A. McMahon) cDNA clones. At least three independent
hybridizations for each probe were tested at each developmental stage.
Cecal and epithelial explant cultures
Embryos from wild-type C57BL/6J mice were dissected at E12.5. The cecums
were removed from the GI tract and embedded in Growth Factor Reduced
MatrigelTM (BD Biosciences) diluted 1:1 with culture medium (5% FCS, 50%
DMEM:F12, penicillin/streptomycin + L-glutamine) in 24-well tissue culture
plates (Burns et al., 2004). To
isolate the epithelium, distal intestines were treated with 5 mg/ml
collagenase A for 5 minutes on ice, and mesenchyme was removed using tungsten
needles. The isolated epithelium was embedded in Growth Factor Reduced
MatrigelTM, as described above. Human FGF10 (100 ng/ml; PeproTech), mouse
FGF9 (100 ng/ml; PeproTech), or BSA (0.1%) soaked heparin-coated beads (Sigma)
were placed one bead diameter away from the cecal explant. MatrigelTM was
allowed to solidify at 37°C for 30 minutes, then 250 µl of culture
medium was gently added to each well and the explants were grown for 4 days at
37°C in a 5% CO2 incubator. For histology, the cultured cecal
explants were fixed overnight in 4% PFA/PBS, embedded in OCT, and 6-um frozen
sections were cut for H&E staining.
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RESULTS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). To examine the spatial patterns of Fgf9 expression
along the length of the GI tract, whole-mount in situ hybridization of
dissected intestines was performed at E11.5-E14.5. At these developmental
stages, Fgf9 was strongly and uniformly expressed throughout the
small intestinal, cecal and colonic epithelium
(Fig. 1A-C, data not shown).
Expression of FGFR1 and FGFR2, potential receptors for FGF9, was localized to
both cecal epithelium and mesenchyme (Fig.
1D-F'). In cecal mesenchyme, FGFR1 was broadly expressed,
whereas FGFR2 showed higher expression on the caudal side of the cecal
bud.
Absent cecal development in Fgf9-/- and Fgf10-/- embryos
The development of the cecum in wild type control,
Fgf9-/- and Fgf10-/- mouse embryos was
examined at E12.5, E14.5 and E18.5. GI tracts from Fgf9+/-
and Fgf10+/- animals were morphologically
indistinguishable from their wild-type littermates at all stages examined
(Fgf9, n=20; Fgf10, n=5, for each genotype at each stage).
At E12.5, the developing cecum is readily identifiable as a
mesothelial-covered, mesenchymal protrusion from the intestinal tract
(Fig. 2A,D). This
characteristic protrusion contains an epithelial bud and occurs at a
distinctive bend in the gut tube at the junction of the distal small intestine
(ileum) and colon. In Fgf9-/- intestines, this
characteristic bend was present at this location, but the mesenchymal bud and
its associated epithelial bud were absent (n=80/80 animals examined;
e.g., Fig. 2A). By contrast,
the ileo-cecal junction of Fgf10-/- mice maintained both
the bend and mesenchymal bud, but lacked epithelial budding into cecal
mesenchyme (n=20/20; e.g. Fig.
2D). In E14.5 wild-type embryos, both the epithelial and
mesenchymal components of the cecum continued to elongate
(Fig. 2B,E,G). At this same
stage, all Fgf9-/- embryos examined showed no evidence of
cecal development (Fig. 2B,H),
whereas all Fgf10-/- embryos studied showed a continued
mesenchymal bud with no epithelial budding (n=20;
Fig. 2E,I). By E18.5, the wild
type embryonic cecum was elongated and showed a mature curved morphology
(Fig. 2C,F).
Fgf9-/- embryos continued to show no cecal development
(Fig. 2C), whereas the
mesenchymal bud of Fgf10-/- embryos appeared to be
degenerating when compared with earlier embryonic time points
(Fig. 2F)
(Burns et al., 2004).
Cell proliferation in the Fgf9-/- embryonic cecum is reduced
Normally, cecal development is initiated at 
E11.5 as a mesenchymal bud
at the ileo-colonic junction. By E12.5, epithelial budding was evident in
control but not Fgf9-/- tissue
(Fig. 3A,B). Therefore, we
assessed mesenchymal and epithelial cell proliferation at E12.5 by BrdU
incorporation. Compared with wild-type tissue, cell proliferation in
Fgf9-/- cecum was reduced by 40% in epithelium and 47% in
mesenchyme (Fig. 3,
Table 1). Interestingly,
mesenchymal proliferation in the cecal buds of wild-type mice was
significantly greater than mesenchymal proliferation in the adjacent small
intestine (Fig. 3,
Table 1). By contrast,
mesenchymal proliferation in Fgf9-/- cecal buds was
significantly less than mesenchymal proliferation in the adjacent small
intestine or colon (Table 1).
Additionally, epithelial proliferation in Fgf9-/- cecal
buds was less than epithelial proliferation in the small intestine or colon
(Table 1). Comparable analysis
of proliferation in the distal small intestine and colon revealed no
significant difference between wild-type and Fgf9-/- mice
in either mesenchyme or epithelium (Table
1). Together, these observations indicate that epithelial
expression of FGF9 is required, either directly or indirectly, for the proper
regulation of both mesenchymal and epithelial proliferation in the cecal
region.
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). To
examine the relationship between epithelial expression of Fgf9 and
mesenchymal expression of Fgf10, Fgf10 expression was examined by
whole-mount in situ hybridization at E11.5 and E12.5. In wild-type embryos,
Fgf10 was expressed in caudal cecal mesenchyme
(Fig. 4A,C). However, in
Fgf9-/- embryos, Fgf10 expression was absent in
mesenchyme at the ileo-colonic junction (n=6; e.g.
Fig. 4B,D). These observations
suggest that Fgf10 expression in cecal mesenchyme requires epithelial
FGF9 signaling. Interestingly, in Fgf10-/- embryos,
epithelial Fgf9 continued to be expressed in the ileo-colonic
junction (Fig. 4E,F). This
suggests that a reciprocal FGF10 signal is not required to maintain epithelial
Fgf9 expression in the cecum, or in other regions of the GI tract
where Fgf10 is not normally expressed. The possibility of other FGFs
contributing to a reciprocal signal cannot be ruled out at this time.
Specificity of epithelial-mesenchymal signaling by FGF9 and FGF10
Based on the in vitro specificity of FGFs for alternatively spliced FGFRs,
we predict that cecal FGF9 signals specifically to mesenchymal FGFRs, whereas
FGF10 signals specifically to epithelial FGFRs
(Ornitz and Itoh, 2001). An
interesting exception to this rule is that FGF9 is able to activate the
epithelial splice form of FGFR3 (FGFR3b) in vitro
(Ornitz et al., 1996);
however, this has not been demonstrated in vivo.
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;
Roberts et al., 1995;
Roberts et al., 1998). Both
SHH and BMP4 signals are known to interact with FGF signaling pathways in lung
and limb development (Bellusci et al.,
1997; Bellusci et al.,
1996; Buckland et al.,
1998; Khokha et al.,
2003; Lebeche et al.,
1999; Scherz et al.,
2004; Weaver et al.,
2000; Zuniga et al.,
1999). To determine whether Shh or Bmp4
expression was affected by the loss of Fgf9 or Fgf10, we
examined their expression at E12.5 and E13.5. In wild-type embryos,
Bmp4 was strongly expressed in cecal mesenchyme
(Fig. 7A,B). Its expression did
not change in the absence of Fgf10
(Fig. 7C,D) (Burns et al., 2004). However,
in Fgf9-/- gut, Bmp4 expression was absent in
ileo-colonic junctional mesenchyme (Fig.
7E,F). In contrast to Bmp4, Shh expression was not
changed in the cecum, small intestine or colonic epithelium in embryos lacking
either Fgf9 or Fgf10
(Fig. 7G,H).
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DISCUSSION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). These
biotransformations include breakdown of plant polysaccharides that are
delivered to the distal gut from the small intestine that otherwise could not
be broken down because the mammalian host lacks the requisite glycoside
hydrolases (Backhed et al.,
2005). The factors that underlie proper cecal development have
been poorly defined. Our data provide new evidence that epithelial-expressed
FGF9 functions primarily to regulate cecal mesenchymal
proliferation/differentiation, as well as mesenchymal FGF10 expression.
Fig. 8 and the discussion below
summarize our view about how FGF9 and FGF10 act in a cooperative and
reciprocal manner, together with other factors, to generate a cecum from the
developing gut tube.
The GI tract consists of functionally distinct domains along the
rostrocaudal axis (esophagus, stomach, small intestine and colon). A muscular
sphincter that regulates the passage of intestinal contents from one region to
the next separates each intestinal domain. Formation of these sphincters is
controlled by regionally specific expression of transcription factors (HOX
genes) and morphogens (Smith and Tabin,
1999; Zakany and Duboule,
1999). HOX genes, which are collinearly expressed along the length
of the GI tract, can be spatially and temporally correlated with morphological
specialization, suggesting that they may pattern the GI tract along the
rostrocaudal axis (Kawazoe et al.,
2002; Pitera et al.,
1999; Roberts,
2000; Sekimoto et al.,
1998; Yokouchi et al.,
1995). In addition to regional specification by these early
patterning genes, epithelial-mesenchymal interactions function to further
guide gut morphogenesis.
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). Despite
this fact, loss of FGF9 has region-specific effects along the rostrocaudal
axis (i.e. a loss of cecal development). In contrast to Fgf9, Fgf10
is expressed at multiple, specific mesenchymal sites along the rostrocaudal
axis, including the pyloric, ileo-colonic and ano-rectal junctions
(Burns et al., 2004;
Fairbanks et al., 2004). FGF10
signals to an epithelial receptor, FGFR2b, and both Fgf10 and
Fgfr2b mutant mice fail to develop a cecal epithelial bud
(Burns et al., 2004). This is
consistent with (1) known roles for FGF10 in inducing epithelial branching in
the lung and salivary glands (Min et al.,
1998; Sekine et al.,
1999; Steinberg et al.,
2005), and (2) our observation that an FGF10 bead can induce the
elongation of intestinal epithelium in the absence of intestinal
mesenchyme. The ileo-colonic junction is characterized by a distinct bend in the GI tract and the formation of the cecum as an intestinal appendage. This ileo-colonic bend is maintained in both Fgf9-/- and Fgf10-/- embryos. Furthermore, Bmp4 expression is absent in the Fgf9-/- ileo-colonic junction. Therefore, this signaling molecule is also not required to specify this boundary. Cecum development initiates as a mesenchymal bud that precedes the budding and elongation of the intestinal epithelium. Examination of the effects of both gain and loss of FGF9 activity on cecal development demonstrates that Fgf9 signals to GI mesenchyme at the ileo-colonic junction, where it induces mesenchymal proliferation. It is necessary for FGF10 expression, and through FGF10, induces epithelial budding and elongation (Fig. 8).
The expression pattern of Fgf9 and the phenotype of Fgf9-/- mice suggest that FGF9 acts as a signal that drives the progression of a predetermined developmental program. In the case of cecal development, FGF9 is necessary for mesenchymal expansion and Fgf10 expression, but FGF9 does not induce significant mesenchymal growth, or expression of Fgf10, in other regions of the small intestine. This suggests that permissive domains for mesenchymal growth and Fgf10 expression are determined by other factors, possibly HOX genes in combination with other signaling molecules (Fig. 8).
In several examples of organogenesis, epithelial and mesenchymal FGFs
exhibit reciprocal signaling. However, the regulation of these reciprocal
signals differs in each developmental situation. In limb bud development,
mesenchymal FGF10 signals to the apical ectodermal ridge; epithelial FGFs 4,
8, 9 and 17, in turn, signal back to limb mesenchyme. This reciprocal FGF
signaling is required for limb development
(Martin, 1998). In the lung,
epithelial FGF9 signals to its mesenchymal receptors, FGFR1c and FGFR2c, and
is crucial for mesenchymal proliferation and Fgf10 expression
(Colvin et al., 2001b)
(A.C.W., unpublished). Mesenchymal FGF10, in turn, signals to epithelial
FGFR2b to induce epithelial branching morphogenesis
(Arman et al., 1999;
Bellusci et al., 1997;
Min et al., 1998;
Park et al., 1998;
Sekine et al., 1999). In the
lung, FGF9 is necessary for FGF10 expression, but is not the primary
determinant of the pattern of Fgf10 expression. Overexpression of
FGF9 in the lung can induce the expression of FGF10 throughout lung
mesenchyme. However, in the intestine, FGF9 can only induce FGF10 in cecal
mesenchyme.
A reciprocal signal is also required to maintain cecal development, because in Fgf10-/- embryos, which lack cecal epithelial branching, the cecal mesenchymal bud degenerates by late gestation. It is possible that low-level Fgf9 expression in cecal epithelium or other FGF10-induced epithelial factors act as survival signals for cecal mesenchyme at later stages of development and that a cecal bud lacking epithelium has insufficient survival factors to maintain cecal mesenchyme. This reciprocal signaling between cecal epithelium and mesenchyme is similar to limb bud development; however, there are also important differences between cecal and limb bud development. In the limb, FGF10 is required to initiate formation of the apical ectodermal ridge, expression of epithelial FGFs and subsequent mesenchymal expansion. By contrast, in cecal development, Fgf10 expression appears to be secondary to epithelial FGF activity and mesenchymal growth.
Finally, understanding details of FGF-mediated signaling in the developing
gut should prove useful in understanding and/or manipulating injury responses
in the adult intestine. For example, exogenously introduced FGFs ameliorate
damage from irradiation (Paris et al.,
2001) or chemical injury (dextran sodium sulfate)
(Chen et al., 2002;
Jeffers et al., 2002). Further
understanding of the cells that express specific FGFs and their receptors in
the adult epithelium and underlying mesenchyme, particularly in the region of
the crypt base where epithelial stem cells reside, could provide more specific
therapeutic tools to prevent or repair damage to the intestinal mucosa.
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