|
|
|
|
|
|
|
||||
| Home Help Feedback Subscriptions Archive Search Table of Contents | ||||
First published online 26 January 2006
doi: 10.1242/dev.02252
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Department of Cell and Molecular Biology, Göteborg University,
Göteborg, Sweden.
2 Department of Biochemistry, Hamamatsu University School of Medicine,
Hamamatsu, Japan.
3 The Electron Microscopy Unit, Department of Anatomy and Cell Biology,
Göteborg University, Göteborg, Sweden.
* Author for correspondence (e-mail: peter.carlsson{at}molbio.gu.se)
Accepted 15 December 2005
 |
SUMMARY |
|---|
 TOP SUMMARY INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Key words: Forkhead, Intestine, Hedgehog, Wnt, Bmp
|
INTRODUCTION |
|---|
|
TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
; Roberts et al.,
1998; Sukegawa et al.,
2000). The mesenchyme produces several factors that control
proliferation, apoptosis and morphogenesis in the epithelium. The canonical
Wnt pathway activates expression of target genes for Tcf transcription factors
in epithelial cells through inhibition of ß-catenin degradation, and an
unequal distribution of ß-catenin activity shapes the pattern of
proliferation and cell migration along the crypt-villus axis
(Batlle et al., 2002;
van de Wetering et al., 2002).
The importance of Wnt signaling for driving the intestinal developmental
program in the endoderm is also illustrated by conversion of lung epithelium
into an intestine-like phenotype by ectopic activation of the Wnt pathway
(Okubo and Hogan, 2004). Bmps
contribute to radial patterning of the gut
(Sukegawa et al., 2000) and
restrict epithelial (Haramis et al.,
2004) as well as mesenchymal
(Roberts et al., 1998)
proliferation.
Forkhead transcription factors participate in specification of the
different mesodermal subpopulations that arise during gastrulation. For
example are Foxc genes expressed in paraxial mesoderm and required for
somitogenesis (Kume et al.,
2001; Wilm et al.,
2004), whereas Foxa2 is essential for formation of the
axial mesoderm (notochord) (Ang and
Rossant, 1994; Weinstein et
al., 1994). The lateral – and later splanchnic –
mesoderm expresses Foxf genes (Aitola et
al., 2000; Mahlapuu et al.,
2001b; Mahlapuu et al.,
1998; Ormestad et al.,
2004; Peterson et al.,
1997), but little is known about their role in specification and
differentiation of this tissue.
Foxf1 is required for completing the split of the lateral plate
into a splanchnic and a somatic component
(Mahlapuu et al., 2001b);
expression of Irx3 – a marker for somatic mesoderm –
expands into the splanchnic layer and coelom formation is defective in
Foxf1-/- embryos
(Mahlapuu et al., 2001b).
Embryonic lethality of null mutants precludes evaluation of the role of
Foxf1 at later stages of gut development, but in lung and foregut its
expression is activated by exogenous Shh, and lung hypoplasia in heterozygotes
suggests that Foxf1 mediates the mitogenic effect of Shh on the
mesenchyme (Mahlapuu et al.,
2001a). Morpholino knockdown of Xenopus Foxf1 interferes
with gut coiling and inhibits development of intestinal smooth muscle cells
(Tseng et al., 2004).
Drosophila has a single Foxf gene, biniou. Similar to
murine Foxf1, biniou is required for the separation between
splanchnic and somatic mesoderm, and like its Xenopus ortholog it is
essential for differentiation of the gut musculature
(Zaffran et al., 2001). Foxf
genes thus appear to have been involved in coelom formation and gut
morphogenesis in organisms that predate the protostome-deuterostome split,
estimated to have occurred approximately one billion years ago.
The second murine Foxf gene, Foxf2, is also expressed in the
splanchnic mesoderm, but of subordinate importance in early embryonic
development (Aitola et al.,
2000; Ormestad et al.,
2004). In contrast to Foxf1, it is also expressed in the
neural crest, in vasculature of the CNS and in limb mesenchyme. Null mutants
of Foxf2 die at birth (Wang et
al., 2003). A cleft in the secondary palate causes air filling of
the gastrointestinal tract, which is likely to interfere with the ability of
the newborn to breath and suckle, and to be the immediate cause of death.
Here, we investigate the role of murine Foxf genes in gut development and its
relation to paracrine signaling by analyzing the intestinal phenotype of
Foxf2-/- and Foxf1-/+;
Foxf2-/+ compound heterozygote mutants.
|
MATERIALS AND METHODS |
|---|
|
TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
;
Mahlapuu et al., 2001b),
Foxf2 (Wang et al.,
2003) and the Bmp4lacZ knock-in
(Lawson et al., 1999) have
been described elsewhere. All mutants were maintained on a C57Bl/6J
background.
Histology, immunohistochemistry and in situ hybridization
Tissues were fixed in 4% paraformaldehyde and processed either for routine
paraffin or cryosectioning. The following antibodies were used for
immunohistochemistry: collagen I (Biomex), collagen IV (Biomex), laminin
(Abcam), smooth muscle 
-actin (SMA, Sigma, Clone 1A4, Alkaline
Phosphatase conjugate), neurofilament M (Chemicon International), E-cadherin
(Zymed, Clone ECCD-2), ß-catenin (Transduction Laboratories), PCNA (Dako,
Clone PC10), Entactin (NeoMarkers, Clone ELM1), Syndecan1 (Research
Diagnostics, Clone 281-2) and Perlecan (Chemicon International, Clone A7L6).
For detection, biotinylated secondary antibodies were used with
HRP-streptavidine and amplification with TSA Biotin System (NEN Life Science
Products). TUNEL assay was performed as previously described
(Blixt et al., 2000) and X-gal
staining according to Hogan et al. (Hogan
et al., 1994). Automated whole-mount in situ hybridization with
digoxigenin-labeled RNA probes was performed on an InsituPro instrument
(Intavis AG, Germany). The following in situ probes were used: Foxf1
(Mahlapuu et al., 2001b),
Foxf2 (Ormestad et al.,
2004), Wnt5a (IMAGE 3487288), Wnt4 (IMAGE
445179), Wnt11 (IMAGE 349486), Sfrp5 (IMAGE 1395864),
Ptch1 (Goodrich et al.,
1996). Histological staining and electron microscopy followed
standard procedures.
Transfection of primary intestinal fibroblasts
Primary fibroblasts were prepared by tryptic dissociation of the mesenchyme
from E18.5 intestine, plated on glass slides and transfected (Lipofectamine,
Invitrogen) with a plasmid encoding a dominant-negative FoxF protein
(DNA-binding domain only) fused to GFP
(Hellqvist et al., 1998).
Cells were fixed (0.5% formalin in PBS for 5 minutes at room temperature
followed by 100% methanol for 1 minute at –20°C) and stained with
collagen I antiserum (visualized with Alexafluor 568, Molecular Probes) 24
hours post-transfection. Transfected cells were identified by their nuclear
GFP fluorescence and nuclei by DAPI staining.
Explant cultures
Intestine and stomach were dissected from E12.5 and E13.5 embryos, and
cultured on filters as previously described
(Mahlapuu et al., 2001a).
Beads (Affi-gel blue, BioRad) soaked in Bmp4 (10 ng/µl), Noggin (100
ng/µl) (both from R&D Systems) or BSA (as control) were grafted into
the mesenchyme of the explants. For inhibition of hedgehog signaling,
cyclopamine was used in the culture medium at a concentration of 20 µM.
After in vitro culture for 24 hours, explants were fixed briefly in 4%
paraformaldehyde and analyzed by whole-mount in situ hybridization with probes
for Wnt5a, Ptch1, Foxf1 and Foxf2.
|
RESULTS |
|---|
|
TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
). All Foxf2-/- and an estimated 94% of
Foxf1-/+; Foxf2-/+ compound
heterozygotes died shortly after birth (three out of 154 surviving offspring
from Foxf1-/+x Foxf2-/+ crosses
were compound heterozygotes and survived for up to a few weeks).
Foxf1-/+ heterozygotes have increased perinatal mortality
– on some genetic backgrounds exceeding 90% – owing to lung and
foregut malformations (Kalinichenko et
al., 2001; Mahlapuu et al.,
2001a). However, the C57Bl/6J strain used here is particularly
resistant to Foxf1 haploinsufficiency and heterozygotes have
approximately the same survival rate and life expectancy as wild type
(Mahlapuu et al., 2001a). The
inviability of compound heterozygotes therefore represents non-allelic
non-complementation and indicates a functional overlap between Foxf1
and Foxf2. Examination of E18.5 fetuses revealed defects and
malformations in the intestine of Foxf2-/- and
Foxf1-/+; Foxf2-/+, whereas cleft
palate was only observed in Foxf2-/-
(Wang et al., 2003). The two
mutant genotypes had similar intestinal abnormalities and will be collectively
referred to as Foxf mutants. In cases where consistent phenotypic differences
between them were observed, this will be specifically commented on.
Reduced Foxf gene dosage causes aganglionic megacolon
At E18.5 the mesodermal component of the murine intestine has given rise to
fibroblasts in a subepithelial mesenchyme, longitudinal and circular muscular
layers, and a mesothelium that delimits the gut from the coelom
(Fig. 1J). In most Foxf mutant
fetuses, the distal colon was thinwalled and dilated (megacolon;
Fig. 1B,E,F,H,I), and in some
Foxf2-/- ended in a blind sac (intestinal atresia or
imperforate anus; Fig. 1F).
Congenital megacolon in human infants is caused by a defective innervation of
the colon (aganglionic colon or Hirschsprung's disease)
(Carrasquillo et al., 2002) and
we therefore examined the distribution of enteric neurons. Immunostaining for
the neuronal markers neurofilament (Fig.
1L,M) and PGP9.5 (not shown) showed that the innervation of
distended parts of the distal colon in Foxf mutants was weak and patchy. The
reduction in enteric neurons correlated with the degree of colon dilation; in
the worst affected regions, neurons were virtually absent.
The distended distal colon of mutants typically had a flat epithelium and
lacked well-developed fibroblasts or mesothelium
(Fig. 1K). The mesodermal
component instead consisted of a lax disorganized assembly of cells with the
appearance of incompletely differentiated smooth muscle cells (SMCs,
Fig. 1K). The poor development
of the musculature in colon and rectum was confirmed by a faint and incoherent
immunostaining for smooth muscle -actin (SMA;
Fig. 1N,O). Proximal,
non-dilated, parts of the colon maintained a more normal histology, but
generally had a smaller diameter than wild type.
Foxf genes are important for extracellular matrix production by intestinal fibroblasts
Throughout the intestine, Foxf mutants showed signs of poor adhesion
between cells, a defect that was more pronounced in
Foxf2-/- than in Foxf1-/+;
Foxf2-/+. The epithelium, the mesenchyme and the two
muscular layers all separated from each other, and in the worst affected parts
each layer dissolved into individual cells. Spontaneous disintegration and
increased susceptibility to mechanical stress suggested a deficiency in the
extracellular matrix (ECM). When viewed by electron microscopy (TEM), cells of
the colon from Foxf1-/+; Foxf2-/+
mutants appeared loosely assembled (Fig.
2). The basal laminae surrounding SMCs as well as the basement
membrane underneath the epithelium were indistinct and frequently replaced by
gaps of extracellular space (Fig.
2D). Immunohistochemistry revealed a striking deficiency of
fibrillar (type I) as well as sheet-forming (type IV) collagens throughout the
intestines of E18.5 Foxf2-/- mutants
(Fig. 3). Laminin staining was
also weaker, although the reduction was not as dramatic (not shown). In
Foxf1-/+; Foxf2-/+ mutants the ECM
staining was reduced (Fig. 3D),
but to a lesser degree than in Foxf2-/-. The compound
heterozygote also had ectopic expression of smooth muscle -actin in
intravillus mesenchyme (Fig.
3M).
|
)
(Fig. 3P,Q). Immunostaining
showed abundant collagen I in ER vesicles of untransfected cells, as well as
in fibers on the growth surface underneath. Transfected cells –
identified by their GFP positive nuclei – contained almost no collagen I
and similar results were obtained for collagen IV (not shown). Expression of
GFP had no effect on collagen production
(Fig. 3N,O). These results
suggest that inhibiting transcriptional regulation of Foxf target genes leads
to loss of collagen synthesis and indicates a cell-autonomous requirement for
Foxf proteins in ECM production by fibroblasts.
ECM deficiency leads to epithelial depolarization and inter-villus adhesion, but surprisingly little apoptosis
Polarization of epithelial cells is induced by interaction with the
basement membrane through integrin receptors
(Kedinger et al., 2000) and an
expected consequence of the ECM deficiency in Foxf mutants was therefore loss
of polarity. Indeed, epithelial cells in Foxf mutants showed typical signs of
depolarization: rounded in shape with central, rather than basal, nuclei. This
anomaly was apparent also in areas where the physical integrity was not yet
affected. The subcellular distribution of E-cadherin, a component of adherence
junctions normally confined to lateral membranes of epithelial cells, expanded
into the basal and apical membranes, and in the most depolarized cells was
circumferentially distributed (Fig.
4D-F). A similar shift from lateral to more or less ubiquitous
membrane staining was also observed for ß-catenin, another component of
adherence junctions. One consequence of cell adhesion proteins being exposed
on the apical surface is adherence between epithelial cells from separate
villi. In areas with overt depolarization the result was extensive
inter-villus cross-linking, which lead to complete luminal obstruction
(Fig. 4C).
|
).
This is illustrated by the presence of apoptotic cells in sites of poor
epithelio-mesenchymal contact of wild-type intestine
(Fig. 4K). Surprisingly, TUNEL
assay did not reveal the expected massive apoptosis in
Foxf2-/- mutants, in spite of the severe deficiency of
several ECM components (Fig.
4L). Loosely attached, completely depolarized cells failed to
undergo apoptosis, and only in areas that had reached the final stages of
tissue disintegration did the frequency of TUNEL-positive cells increase
significantly (Fig. 4M).
|
).
The large clusters of epithelial cells in Foxf1-/+;
Foxf2-/+ small intestine, particularly in the distal parts
of villi, therefore suggested overproliferation or loss of normal control of
cell survival. Epithelial proliferation in E18.5 small intestine is confined
to the intervillus pockets, predecessors of crypts of Lieberkühn which do
not form until postnatally. Transition from the basal, proliferative to the
distal, postmitotic, compartment is indicated by loss of proliferation markers
such as PCNA (Fig. 4G). In Foxf
mutants, the sharp boundary between proliferating and non-proliferating cells
was dissolved and PCNA-positive cells were found throughout the villi
(Fig. 4H,I). Persistent cell
division therefore appears to account for the observed surplus of epithelial
cells.
|
How does a decreased Foxf expression in the mesenchyme lead to
ß-catenin stabilization in the epithelium? In mice lacking
Foxl1, another mesenchymal forkhead gene, accumulation of
proteoglycans has been suggested to facilitate Wnt signaling and thereby
promote epithelial overgrowth (Kaestner et
al., 1997; Katz et al.,
2004; Perreault et al.,
2001). However, in Foxf mutants, the major intestinal
proteoglycans were present in normal (perlecan and nidogen/entactin) or
reduced (syndecan 1) amounts (Fig.
5L-Q). We therefore investigated if a reduced Foxf gene dose
increases the expression of Wnt genes in the mesenchyme. To exclude secondary
effects due to interrupted epithelio-mesenchymal signaling, E14.5 embryos were
chosen – a stage at which the association between epithelium and
mesenchyme is still intact in the mutants. Whole-mount in situ hybridization
with candidate Wnt genes (Wnt4, Wnt5a and Wnt11) showed
Wnt5a to be upregulated in Foxf2-/- embryos
(Fig. 6A). Wnt5a and
Foxf2 are co-expressed in several parts of the embryo, such as limbs
and genital tubercle, and an increase in Wnt5a mRNA was seen in all
these organs of Foxf2-null embryos, with intermediate levels in
Foxf2-/+ heterozygotes (not shown). In fact, the
difference in Wnt5a mRNA content between Foxf2-/-
and wild type was greater in limbs, where Foxf2 is the only expressed
Foxf gene, than in the intestine where Foxf1 and Foxf2 are
co-expressed.
|
) and its
expression in the early splanchnic mesoderm requires Foxf1
(Mahlapuu et al., 2001b). We
first compared Bmp4 expression in Foxf2-/- and
wild-type using a Bmp4lacZ knock in. ß-galactosidase
activity in the intestine of Foxf2-/-;
Bmp4lacZ/+ embryos (E15.5) was reduced
(Fig. 6B,C) in the gut, whereas
tissues without Foxf expression, such as eye lids and hair follicles, retained
normal Bmp4-driven ß-galactosidase activity
(Fig. 6D,E). To investigate if
Bmp signaling influences Wnt5a expression in the intestinal
mesenchyme, we applied beads soaked in Bmp4 or the Bmp antagonist Noggin to
the mesenchyme of gastric or intestinal explants (E12.5 or 13.5), cultured in
vitro and analyzed Wnt5a expression by whole-mount in situ
hybridization (Fig. 6F-J). Bmp4
inhibited Wnt5a expression in Foxf2-/- explants
(Fig. 6H,I), and Noggin induced
high levels of Wnt5a mRNA in wild-type explants, from a low basal
expression (Fig. 6J). By
contrast, Foxf gene expression was not influenced by Bmp4 or Noggin (not
shown).
|
|
). The
overlapping expression of Shh and Ihh, together with the
early lethality of the double null mutant, limit the use of genetic methods to
evaluate the role of hedgehogs in activation of Foxf genes in the intestine.
Instead, we used cyclopamine to inhibit hedgehog signaling in explant
cultures. Cyclopamine was found to reduce the expression of both
Foxf1 and Foxf2 to the same extent as of a known hedgehog
target, Ptch1 (Fig.
6K-P). We therefore conclude that Shh and Ihh from the epithelium
activates mesenchymal transcription of Foxf genes also in the intestine. |
DISCUSSION |
|---|
|
TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
) of a
role in gut development implies that this represents an ancient and presumably
primeval role of the FoxF class of forkhead transcription factors.
Phenotypic similarity between Foxf2-/- and the
Foxf1; Foxf2 compound heterozygotes indicates a functional
overlap between the two proteins. Rather than redundancy, the relation between
Foxf1 and Foxf2 represents non-allelic non-complementation,
as at least three functional alleles are required for normal development.
However, although functionally overlapping, the presence of phenotypic
differences between the mutants also indicates non-equivalence, in agreement
with the distinct properties of the activation domains shown previously
(Hellqvist et al., 1998;
Hellqvist et al., 1996;
Mahlapuu et al., 1998). The
more severe ECM deficiency in Foxf2-/- may explain the
strikingly different small intestine histology of the two mutants. Both share
an activation of the canonical Wnt pathway, presence of cycling cells in the
distal parts of villi and a partial resistance to apoptosis in cells with poor
anchorage. In the presence of an intact, although weakened, basement membrane
this will allow accumulation of excessive epithelial cells – as seen in
the compound heterozygote – whereas loss of contact between epithelium
and mesenchyme will impede Wnt signaling, lead to less proliferation and the
more severe disintegration typical of Foxf2-/-.
Regions with disintegrated tissues and crosslinked villi can be found next to areas with a grossly normal histology. This rules out difference in genetic background as the sole source of phenotypic variation and instead suggests that reduction of Foxf gene dose creates an unstable situation that will deteriorate rapidly once the defects reach a certain level. Hedgehog signaling from epithelium to mesenchyme requires an intimate contact between cells and will be hampered by loss of ECM. With Foxf genes activated by hedgehog, a degenerative cycle may be initiated once the epithelio-mesenchymal contact is disturbed: lower expression from the remaining Foxf alleles would produce even less ECM and gradually aggravate the tissue disintegration (Fig. 7). Initial small differences in the contact between cells – enough to trigger a degenerative cycle in some areas, but not in others – may be introduced when cell adhesion is challenged by the forces of the commencing peristalsis.
Similarities between the hedgehog and Foxf mutant phenotypes
suggest that reduced Foxf expression is responsible for many of the observed
defects in hedgehog mutants, such as megacolon (in
Ihh-/-), anal atresia (in Shh-/- and
Gli2/3 mutants) and smooth muscle hypoplasia (in
Ihh-/-) (Mo et al.,
2001; Ramalho-Santos et al.,
2000). Inhibition of hedgehog signaling by transgenic expression
of Hhip mimics the phenotype described here, including activation of the
Wnt/ß-catenin pathway, epithelial overproliferation and SMA-positive
cells in the villus core (Madison et al.,
2005). A conserved role for Foxf proteins in intestinal smooth
muscle development is further supported by the loss of gut SMCs in response to
Foxf1 morpholino knockdown in Xenopus embryos
(Tseng et al., 2004) and the
defective visceral musculature in Drosophila biniou mutants
(Zaffran et al., 2001).
The posterior gut agangliosis, which Foxf mutants share with
Ihh-/- (Ramalho-Santos
et al., 2000), resembles Hirschsprung's disease in humans
(Carrasquillo et al., 2002).
Bmp4 inhibits enteric nerve differentiation
(Sukegawa et al., 2000), and
premature differentiation of migrating, neural crest-derived neuronal
precursors – as a result of decreased Bmp4 expression –
could lead to their depletion preferentially in the posterior gut. SMCs
produce a neurotrophic factor, neurturin, that stimulates growth of enteric
nerves (Rossi et al., 1999);
therefore smooth muscle hypoplasia may also contribute to the reduction of
neurons.
Wnt5a can activate both the canonical and non-canonical pathways
(Civenni et al., 2003;
Topol et al., 2003), and the
specificity appears to reside in the receptor. When acting through the Fzd5
receptor, Wnt5a is a potent activator of the canonical pathway and induces
axis duplication in Xenopus embryos
(He et al., 1997;
Ishikawa et al., 2001).
Fzd5 is expressed in epithelial cells throughout the murine
intestine, with highest expression in the crypts
(Ishikawa et al., 2001).
Activation of the canonical pathway with stabilized ß-catenin in the
epithelium is therefore an expected result of increased expression of
Wnt5a in the mesenchyme.
That Bmps in the intestine are involved in limiting epithelial
proliferation is illustrated by formation of ectopic crypts and adenomatous
foci in response to transgenic overexpression of noggin (Nog)
(Haramis et al., 2004).
However, in contrast to Foxf mutants, Nog-transgenic animals develop
normally up until 3 weeks postnatally and the abnormal proliferation takes
place in crypt-like structures, rather than throughout the villi. Hence,
lowering Foxf gene dose appears to have a pleiotropic effect on cell
signaling, and mechanisms other than those caused by a reduction of
Bmp4 expression are likely to contribute to the mutant phenotype.
Deregulation of epithelial proliferation, contact inhibition and survival
are hallmarks of intestinal carcinoma and the genetic lesions in epithelial
cells that underlie cancerous transformation have been studied extensively
(Reya and Clevers, 2005).
However, recent results show that the environment provided by the tumor stroma
(i.e. non-epithelial cells) influences not only tumor progression but also
initiation, and that alterations in both growth factor signaling and ECM
composition are important (Bhowmick et al.,
2004; Kuperwasser et al.,
2004). The tumor-associated, growth-promoting fibroblasts are
referred to as `activated' and, although the exact nature of the underlying
changes are not known, activated fibroblasts normally express myofibroblastic
markers, such as SMA. The expression of SMA in the subepithelial and
intra-villus fibroblast layer of Foxf mutants suggests that there may be a
common mechanistic basis for certain changes in epithelial growth and survival
seen in Foxf mutants and in intestinal carcinoma. The expansion of
SMA-positive myofibroblasts into the villus core in response to transgenic
inhibition of hedgehog signaling (Madison
et al., 2005) is consistent with this model.
Foxl1 is expressed in intestinal fibroblasts and – like Foxf
genes – controls ß-catenin accumulation in epithelial cells,
although by a different mechanism
(Kaestner et al., 1997;
Perreault et al., 2001). Loss
of both Foxl1 alleles on an Apc-/+ (Min)
genetic background leads to a marked increase in tumor multiplicity in the
colon, and ApcMin/+; Foxl1-/- mice
also develop gastric tumors not observed in ApcMin/+ mice
(Perreault et al., 2005). The
fact that Foxf mutants have an increased intestinal Wnt signaling and that
fibroblasts express a marker characteristic of activated tumor stroma raise
the possibility that loss of Foxf alleles could contribute to tumor
susceptibility.
|
ACKNOWLEDGMENTS |
|---|
|
REFERENCES |
|---|
|
TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Aitola, M., Carlsson, P., Mahlapuu, M., Enerback, S. and Pelto-Huikko, M. (2000). Forkhead transcription factor FoxF2 is expressed in mesodermal tissues involved in epithelio-mesenchymal interactions. Dev. Dyn. 218,136 -149.[CrossRef][Medline]
Ang, S. L. and Rossant, J. (1994). HNF-3 beta is essential for node and notochord formation in mouse development. Cell 78,561 -574.[CrossRef][Medline]
Batlle, E., Henderson, J. T., Beghtel, H., van den Born, M. M., Sancho, E., Huls, G., Meeldijk, J., Robertson, J., van de Wetering, M., Pawson, T. et al. (2002). Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB. Cell 111,251 -263.[CrossRef][Medline]
Bhowmick, N. A., Chytil, A., Plieth, D., Gorska, A. E., Dumont,
N., Shappell, S., Washington, M. K., Neilson, E. G. and Moses, H. L.
(2004). TGF-beta signaling in fibroblasts modulates the oncogenic
potential of adjacent epithelia. Science
303,848
-851.
Blixt, Å., Mahlapuu, M., Aitola, M., Pelto-Huikko, M.,
Enerbäck, S. and Carlsson, P. (2000). A forkhead gene,
FoxE3, is essential for lens epithelial proliferation and closure of
the lens vesicle. Genes Dev.
14,245
-254.
Carrasquillo, M. M., McCallion, A. S., Puffenberger, E. G., Kashuk, C. S., Nouri, N. and Chakravarti, A. (2002). Genome-wide association study and mouse model identify interaction between RET and EDNRB pathways in Hirschsprung disease. Nat. Genet. 32,237 -244.[CrossRef][Medline]
Civenni, G., Holbro, T. and Hynes, N. E. (2003). Wnt1 and Wnt5a induce cyclin D1 expression through ErbB1 transactivation in HC11 mammary epithelial cells. EMBO Rep. 4,166 -171.[CrossRef][Medline]
Frisch, S. M. and Ruoslahti, E. (1997). Integrins and anoikis. Curr. Opin. Cell Biol. 9, 701-706.[CrossRef][Medline]
Goodrich, L. V., Johnson, R. L., Milenkovic, L., McMahon, J. A.
and Scott, M. P. (1996). Conservation of the hedgehog/patched
signaling pathway from flies to mice: induction of a mouse patched gene by
Hedgehog. Genes Dev. 10,301
-312.
Haramis, A. P., Begthel, H., van den Born, M., van Es, J.,
Jonkheer, S., Offerhaus, G. J. and Clevers, H. (2004). De
novo crypt formation and juvenile polyposis on BMP inhibition in mouse
intestine. Science 303,1684
-1686.
He, X., Saint-Jeannet, J. P., Wang, Y., Nathans, J., Dawid, I.
and Varmus, H. (1997). A member of the Frizzled protein
family mediating axis induction by Wnt-5A. Science
275,1652
-1654.
Hellqvist, M., Mahlapuu, M., Samuelsson, L., Enerback, S. and
Carlsson, P. (1996). Differential activation of lung-specific
genes by two forkhead proteins, FREAC-1 and FREAC-2. J. Biol.
Chem. 271,4482
-4490.
Hellqvist, M., Mahlapuu, M., Blixt, A., Enerback, S. and
Carlsson, P. (1998). The human forkhead protein FREAC-2
contains two functionally redundant activation domains and interacts with TBP
and TFIIB. J. Biol. Chem.
273,23335
-23343.
Hogan, B., Beddington, R., Costantini, F. and Lacy, E. (1994). Manipulating the Mouse Embryo: A Laboratory Manual. New York: Cold Spring Harbor Laboratory Press.
Ishikawa, T., Tamai, Y., Zorn, A. M., Yoshida, H., Seldin, M. F., Nishikawa, S. and Taketo, M. M. (2001). Mouse Wnt receptor gene Fzd5 is essential for yolk sac and placental angiogenesis. Development 128,25 -33.[Abstract]
Kaestner, K. H., Silberg, D. G., Traber, P. G. and Schutz,
G. (1997). The mesenchymal winged helix transcription factor
Fkh6 is required for the control of gastrointestinal proliferation and
differentiation. Genes Dev.
11,1583
-1595.
Kalinichenko, V. V., Lim, L., Stolz, D. B., Shin, B., Rausa, F. M., Clark, J., Whitsett, J. A., Watkins, S. C. and Costa, R. H. (2001). Defects in pulmonary vasculature and perinatal lung hemorrhage in mice heterozygous null for the Forkhead Box f1 transcription factor. Dev. Biol. 235,489 -506.[CrossRef][Medline]
Katz, J. P., Perreault, N., Goldstein, B. G., Chao, H. H.,
Ferraris, R. P. and Kaestner, K. H. (2004). Foxl1 null mice
have abnormal intestinal epithelia, postnatal growth retardation, and
defective intestinal glucose uptake. Am J. Physiol. Gastrointest.
Liver Physiol. 287,G856
-G864.
Kedinger, M., Freund, J., Launay, J. and Simon-Assman, P. (2000). Cell Interactions through the basement membrane in intestinal development and differentiation. In Development of the Gastrointestinal Tract (ed. I. R. Sanderson and W. A. Walker), pp. 83-102. Hamilton: B. C. Decker.
Kume, T., Jiang, H., Topczewska, J. M. and Hogan, B. L.
(2001). The murine winged helix transcription factors, Foxc1 and
Foxc2, are both required for cardiovascular development and somitogenesis.
Genes Dev. 15,2470
-2482.
Kuperwasser, C., Chavarria, T., Wu, M., Magrane, G., Gray, J.
W., Carey, L., Richardson, A. and Weinberg, R. A. (2004).
Reconstruction of functionally normal and malignant human breast tissues in
mice. Proc. Natl. Acad. Sci. USA
101,4966
-4971.
Lawson, K. A., Dunn, N. R., Roelen, B. A., Zeinstra, L. M.,
Davis, A. M., Wright, C. V., Korving, J. P. and Hogan, B. L.
(1999). Bmp4 is required for the generation of primordial germ
cells in the mouse embryo. Genes Dev.
13,424
-436.
Madison, B. B., Braunstein, K., Kuizon, E., Portman, K., Qiao,
X. T. and Gumucio, D. L. (2005). Epithelial hedgehog signals
pattern the intestinal crypt-villus axis. Development
132,279
-289.
Mahlapuu, M., Pelto-Huikko, M., Aitola, M., Enerback, S. and Carlsson, P. (1998). FREAC-1 contains a cell-type-specific transcriptional activation domain and is expressed in epithelial-mesenchymal interfaces. Dev. Biol. 202,183 -195.[CrossRef][Medline]
Mahlapuu, M., Enerback, S. and Carlsson, P. (2001a). Haploinsufficiency of the forkhead gene Foxf1, a target for sonic hedgehog signaling, causes lung and foregut malformations. Development 128,2397 -2406.[Medline]
Mahlapuu, M., Ormestad, M., Enerback, S. and Carlsson, P. (2001b). The forkhead transcription factor Foxf1 is required for differentiation of extra-embryonic and lateral plate mesoderm. Development 128,155 -166.[Abstract]
Mo, R., Kim, J. H., Zhang, J., Chiang, C., Hui, C. C. and Kim,
P. C. (2001). Anorectal malformations caused by defects in
sonic hedgehog signaling. Am. J. Pathol.
159,765
-774.
Okubo, T. and Hogan, B. L. (2004). Hyperactive Wnt signaling changes the developmental potential of embryonic lung endoderm. J. Biol. 3,11 .[CrossRef][Medline]
Ormestad, M., Astorga, J. and Carlsson, P. (2004). Differences in the embryonic expression patterns of mouse Foxf1 and -2 match their distinct mutant phenotypes. Dev. Dyn. 229,328 -333.[CrossRef][Medline]
Perreault, N., Katz, J. P., Sackett, S. D. and Kaestner, K.
H. (2001). Foxl1 controls the Wnt/beta-catenin pathway by
modulating the expression of proteoglycans in the gut. J. Biol.
Chem. 276,43328
-43333.
Perreault, N., Sackett, S. D., Katz, J. P., Furth, E. E. and
Kaestner, K. H. (2005). Foxl1 is a mesenchymal Modifier of
Min in carcinogenesis of stomach and colon. Genes Dev.
19,311
-315.
Peterson, R. S., Lim, L., Ye, H., Zhou, H., Overdier, D. G. and Costa, R. H. (1997). The winged helix transcriptional activator HFH-8 is expressed in the mesoderm of the primitive streak stage of mouse embryos and its cellular derivatives. Mech. Dev. 69, 53-69.[CrossRef][Medline]
Ramalho-Santos, M., Melton, D. A. and McMahon, A. P. (2000). Hedgehog signals regulate multiple aspects of gastrointestinal development. Development 127,2763 -2772.[Abstract]
Reya, T. and Clevers, H. (2005). Wnt signalling in stem cells and cancer. Nature 434,843 -850.[CrossRef][Medline]
Roberts, D. J., Smith, D. M., Goff, D. J. and Tabin, C. J. (1998). Epithelial-mesenchymal signaling during the regionalization of the chick gut. Development 125,2791 -2801.[Abstract]
Rossi, J., Luukko, K., Poteryaev, D., Laurikainen, A., Sun, Y. F., Laakso, T., Eerikainen, S., Tuominen, R., Lakso, M., Rauvala, H. et al. (1999). Retarded growth and deficits in the enteric and parasympathetic nervous system in mice lacking GFR alpha2, a functional neurturin receptor. Neuron 22,243 -252.[CrossRef][Medline]
Stappenbeck, T. S., Wong, M. H., Saam, J. R., Mysorekar, I. U. and Gordon, J. I. (1998). Notes from some crypt watchers: regulation of renewal in the mouse intestinal epithelium. Curr. Opin. Cell Biol. 10,702 -709.[CrossRef][Medline]
Sukegawa, A., Narita, T., Kameda, T., Saitoh, K., Nohno, T., Iba, H., Yasugi, S. and Fukuda, K. (2000). The concentric structure of the developing gut is regulated by Sonic hedgehog derived from endodermal epithelium. Development 127,1971 -1980.[Abstract]
Suzuki, K., Bachiller, D., Chen, Y. P., Kamikawa, M., Ogi, H.,
Haraguchi, R., Ogino, Y., Minami, Y., Mishina, Y., Ahn, K. et al.
(2003). Regulation of outgrowth and apoptosis for the terminal
appendage: external genitalia development by concerted actions of BMP
signaling. Development
130,6209
-6220.
Topol, L., Jiang, X., Choi, H., Garrett-Beal, L., Carolan, P. J.
and Yang, Y. (2003). Wnt-5a inhibits the canonical Wnt
pathway by promoting GSK-3-independent beta-catenin degradation. J.
Cell Biol. 162,899
-908.
Tseng, H. T., Shah, R. and Jamrich, M. (2004).
Function and regulation of FoxF1 during Xenopus gut development.
Development 131,3637
-3647.
van de Wetering, M., Sancho, E., Verweij, C., de Lau, W., Oving, I., Hurlstone, A., van der Horn, K., Batlle, E., Coudreuse, D., Haramis, A. P. et al. (2002). The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 111,241 -250.[CrossRef][Medline]
Wang, T., Tamakoshi, T., Uezato, T., Shu, F., Kanzaki-Kato, N., Fu, Y., Koseki, H., Yoshida, N., Sugiyama, T. and Miura, N. (2003). Forkhead transcription factor Foxf2 (LUN)-deficient mice exhibit abnormal development of secondary palate. Dev. Biol. 259,83 -94.[CrossRef][Medline]
Weinstein, D. C., Ruiz i Altaba, A., Chen, W. S., Hoodless, P., Prezioso, V. R., Jessell, T. M. and Darnell, J. E., Jr (1994). The winged-helix transcription factor HNF-3 beta is required for notochord development in the mouse embryo. Cell 78,575 -588.[CrossRef][Medline]
Wilm, B., James, R. G., Schultheiss, T. M. and Hogan, B. L. (2004). The forkhead genes, Foxc1 and Foxc2, regulate paraxial versus intermediate mesoderm cell fate. Dev. Biol. 271,176 -189.[CrossRef][Medline]
Zaffran, S., Kuchler, A., Lee, H. H. and Frasch, M.
(2001). biniou (FoxF), a central component in a regulatory
network controlling visceral mesoderm development and midgut morphogenesis in
Drosophila. Genes Dev.
15,2900
-2915.
This article has been cited by other articles:
|
|
 |
|
  J. Pan, Z. Lian, S. Wallet, and M. A. Feitelson The hepatitis B x antigen effector, URG7, blocks tumour necrosis factor {alpha}-mediated apoptosis by activation of phosphoinositol 3-kinase and beta-catenin J. Gen. Virol., December 1, 2007; 88(12): 3275 - 3285. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Astorga and P. Carlsson Hedgehog induction of murine vasculogenesis is mediated by Foxf1 and Bmp4 Development, October 15, 2007; 134(20): 3753 - 3761. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. R. van den Brink Hedgehog Signaling in Development and Homeostasis of the Gastrointestinal Tract Physiol Rev, October 1, 2007; 87(4): 1343 - 1375. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Jakobsen, M. Braun, J. Astorga, E. H. Gustafson, T. Sandmann, M. Karzynski, P. Carlsson, and E. E.M. Furlong Temporal ChIP-on-chip reveals Biniou as a universal regulator of the visceral muscle transcriptional network Genes & Dev., October 1, 2007; 21(19): 2448 - 2460. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Li, B. B. Madison, W. Zacharias, A. Kolterud, D. States, and D. L. Gumucio Deconvoluting the intestine: molecular evidence for a major role of the mesenchyme in the modulation of signaling cross talk Physiol Genomics, May 11, 2007; 29(3): 290 - 301. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||
