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First published online 19 September 2007
doi: 10.1242/dev.004432
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Department of Cell and Molecular Biology, Göteborg University, Box 462, SE-405 30 Göteborg, Sweden.
* Author for correspondence (e-mail: peter.carlsson{at}cmb.gu.se)
Accepted 5 August 2007
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SUMMARY |
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 TOP SUMMARY INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key words: Bmp, Forkhead, Hedgehog, Vasculogenesis, Mouse
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INTRODUCTION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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; Jain,
2003).
Vascular endothelial growth factor (Vegf) and its receptor Flk1 (Kdr -
Mouse Genome Informatics) are essential in all blood vessel development -
angiogenesis as well as vasculogenesis - and genetic ablation of either
receptor or ligand leads to a completely avascular phenotype [for a review of
Vegf in vascular development, see Coultas et al.
(Coultas et al., 2005)].
Angioblasts express Flk1 and require Vegf for proliferation, differentiation
and survival. Vegf production is induced by hypoxia and concentration
gradients of Vegf guide vascular sprouts into poorly oxygenated areas
(Gerhardt et al., 2003). In
vitro models and mutant phenotypes in several vertebrate species have
illustrated the involvement of additional growth factor pathways in vascular
development, but the relationships between them are not fully understood.
Bone morphogenetic proteins (Bmps), in particular Bmp4, are required for
mesoderm formation and consequently for development of all mesodermally
derived tissues, including blood vessels
(Mishina et al., 1995;
Winnier et al., 1995). Bmp4
ventralizes mesoderm and is antagonized by dorsal/midline Bmp inhibitors such
as noggin (Harland, 1994). In
vitro, Bmp4 induces formation of Flk1+ Tal1+ cells,
which require Vegf for proliferation and further differentiation
(Park et al., 2004). In quail,
ectopic Bmp4 has been shown to induce vascularization at the midline and
expression of Quek1 (the Flk1 homolog) in the lateral plate
(Reese et al., 2004).
Interpretation of the phenotypes of loss-of-function mutants in mouse is
complicated by the importance of Bmp signaling in gastrulation. However,
Bmp4-null embryos that survive into the somite stage display a
paucity of blood islands and extraembryonic mesoderm in the yolk sac
(Winnier et al., 1995).
Furthermore, targeted inactivation of either of the Bmp signal transducers
Smad1 (Lechleider et al.,
2001; Tremblay et al.,
2001) or Smad5 (Chang et al.,
1999; Yang et al.,
1999) leads to embryonic lethality owing to a defective
vasculature.
Several lines of evidence implicate the hedgehog pathway in vertebrate
blood vessel formation. Inactivation of sonic hedgehog (Shh) is
associated with decreased or defective vascular development
(Brown et al., 2000;
Pepicelli et al., 1998),
whereas its overexpression in neuroectoderm causes hypervascularization
(Rowitch et al., 1999). In
adult mice, Shh stimulates neovascularization
(Pola et al., 2001). In
contrast to ectopic Vegf, which mainly induces endothelial sprouts, Shh
promotes the entire angiogenesis program, including recruitment of mural
cells, remodeling and vascular maturation
(Pola et al., 2001).
Extraembryonic vasculogenesis requires signals from the visceral endoderm and
hedgehog proteins have been shown to be part of this signal. Indian hedgehog
(Ihh) is highly expressed in the murine visceral endoderm
(Becker et al., 1997;
Farrington et al., 1997) and
is the primary hedgehog family member responsible for induction of yolk sac
vasculogenesis. Targeted inactivation of Ihh leads to poor
development of the yolk sac vasculature
(Byrd et al., 2002), which
results in the death of approximately 50% of Ihh-null embryos at
mid-gestation (St-Jacques et al.,
1999). Ihh-/- embryoid bodies are unable to
form blood islands (Byrd et al.,
2002) and recombinant Ihh can substitute for visceral endoderm as
the inducer of vasculogenesis and activator of Bmp4 in tissue recombination
experiments (Dyer et al.,
2001). In chicken embryos, Shh can substitute for endoderm as the
inducer of vascular tube formation (Vokes
et al., 2004).
Different models have been put forward regarding the mechanism through
which hedgehogs induce vascular development. In adult mice, Shh has been
reported not to act directly on the endothelial cells, but rather through
interstitial mesenchymal cells that respond by producing angiopoetins and Vegf
(Pola et al., 2001). Vokes et
al. (Vokes et al., 2004)
suggested that Shh induces embryonic vascular tube formation by directly
influencing the morphological properties of endothelial cells independently of
Vegf.
Here, we use a combination of genetics and in vitro explant culture techniques to determine the mechanisms by which the hedgehog and Bmp signaling pathways regulate extraembryonic vascular tube formation. We show that Foxf1 (also known as Foxf1a - Mouse Genome Informatics), which encodes a forkhead transcription factor, is a mesodermal target for endodermal hedgehog signaling. Foxf1 activates the expression of Bmp4 in mesodermal cells, which in turn induces vascular tube formation. In one tissue undergoing extensive vasculogenesis - the murine allantois - expression of Foxf1 is independent of hedgehog. Allantoic Bmp4 expression and vasculogenesis are unaffected by abrogation of hedgehog signaling through deletion of smoothened (Smo). Genetic inactivation of Foxf1, on the other hand, leads to loss of both Bmp4 expression and vasculogenesis in this tissue, a defect that can be rescued in vitro by exogenous Bmp4. That the same pathway also operates in a tissue where vasculogenesis normally requires hedgehog was shown by the ability of exogenous Bmp4 to rescue vascular plexus formation in Smo-/- yolk sacs.
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MATERIALS AND METHODS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Shhtm1
(Chiang et al., 1996) was
obtained from The Jackson Laboratory (Bar Harbor, ME).
Ihh- and Smo- strains
(St-Jacques et al., 1999;
Zhang et al., 2001) were
kindly provided by Dr A. P. McMahon and a strain carrying the
Bmp4lacZ knock-in allele
(Lawson et al., 1999) was
kindly provided by Dr B. L. M. Hogan. Wild-type mice were C57Bl/6 (Charles
River) and all mutants were maintained by breeding with this strain.
Genotyping was performed by PCR as previously described
(Lawson et al., 1999;
Mahlapuu et al., 2001b;
St-Jacques et al., 1999;
Zhang et al., 2001).
In situ hybridization, immunohistochemistry and histological staining
Embryos heterozygous for the Bmp4lacZ allele were
stained with X-Gal (Hogan et al.,
1994), embedded in paraffin and sectioned. Whole-mount in situ
hybridization was performed as described
(Blixt et al., 2000) with an
antisense RNA probe for Foxf1
(Mahlapuu et al., 2001a). Rat
monoclonal antibodies against Pecam (also known as Pecam1 - Mouse Genome
Informatics) and Flk1 as well as a FITC-conjugated anti-CD41 (Itga2b - Mouse
Genome Informatics) were purchased from BD Biosciences Pharmingen, and the
FITC-conjugated anti-SMA (Acta2 - Mouse Genome Informatics) mouse monoclonal
from Sigma. Detection of rat monoclonal antibodies was by biotinylated
secondary antibodies and either HRP-streptavidin amplification with the TSA TM
Biotin System (NEN Life Science Products) and DAB, or Alexa Fluor-streptavidin
(Molecular Probes) immunofluorescence. Haematoxylin-Eosin (H&E) staining
of paraffin sections was used for general histology.
Explant cultures
Allantoic buds were dissected from E8.25 embryos and cultured on cover
slips for 24 hours in DMEM medium (Gibco) supplemented with 10% fetal calf
serum, L-glutamine (2 mM) and penicillin-streptomycin (10 U/ml) in
5% CO2, 100% humidity. Recombinant Bmp2, 4, 6 and 7 (0.1 ng/ml) and
noggin (1 or 10 ng/ml) (all from R&D systems) were added to the culture
medium when the explant cells had adhered to the substrate (approximately 3
hours after dissection). Yolk sacs were dissected and spread, mesoderm side
up, on MF filters (Millipore), supported by stainless steel grids in 30 mm
culture dishes. Approximately 3 ml of BGJb medium (Life Technologies)
supplemented with 0.2 mg/ml ascorbic acid, 10 U/ml penicillin-streptomycin and
0.1% BSA was added to establish an air-fluid interface at the level of the
explants and the cultures were kept at 37°C in 5% CO2, 100%
relative humidity for 24 hours. All results were verified by repeating the
explant culture experiment at least three times.
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RESULTS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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;
Ormestad et al., 2006). To
investigate whether the same relationship exists in the early mouse embryo, we
analyzed Foxf1 expression in Ihh-/- embryos. Ihh
is the dominating hedgehog in the yolk sac endoderm at the stage when the
extraembryonic vasculature develops. At E9.5, Ihh-/- yolk
sacs had fewer and thinner blood vessels, compared with wild-type (wt)
(Fig. 1A,B)
(Byrd et al., 2002). The
reduced vasculature causes resorption of approximately 50% of
Ihh-null embryos before establishment of a placental circulation,
whereas the rest develop to term
(St-Jacques et al., 1999).
This contrasts with Foxf1-/- embryos, which have a fully
penetrant avascular yolk sac phenotype
(Fig. 1C) and are invariably
resorbed by E10.5 (Mahlapuu et al.,
2001b). Judged by whole-mount in situ hybridization,
Foxf1 expression was reduced in Ihh-/- blood
islands, which at E8.5 appeared as a freckled staining pattern on the wt yolk
sac surface (Fig. 1F,G). No
alterations in expression pattern were observed in allantoic or lateral
mesoderm (Fig. 1D,E).
The persistence of Foxf1 mRNA in Ihh-/-
embryos raised questions about whether, at this stage, Foxf1
expression is independent of hedgehogs, or if other hedgehogs might compensate
for the loss of Ihh. The severe phenotype of Shh-/-;
Ihh-/- embryos, as compared with either single mutant,
indicates a widespread redundancy and a role for Ihh in processes previously
thought to require only Shh (Zhang et al.,
2001). Similarly, Shh might play a minor, but - in the absence of
Ihh - significant, role in yolk sac development. We therefore analyzed
Shh-/-; Ihh-/- embryos and found their
yolk sacs to be thin, transparent and essentially avascular
(Fig. 2B,D). This indicates
that Shh and Ihh both contribute to induction of yolk sac vasculogenesis.
Closer inspection revealed adhesion between amnion and yolk sac in the
hedgehog double mutants (arrowheads in Fig.
2B,D), which is reminiscent of the extensive adherences observed
in extraembryonic mesoderm of Foxf1 mutant embryos
(Mahlapuu et al., 2001b). No
Foxf1 mRNA could be detected in yolk sac or lateral mesoderm of
hedgehog double-null embryos. However, the allantois and the most-posterior
embryonic mesoderm, exiting from the posterior primitive streak, expressed
Foxf1 (Fig. 2F).
The wrinkles on the E9.5 Foxf1-/- yolk sac surface
(Fig. 1C) could be mistaken for
blood vessels, but actually consist of folds in the visceral endoderm that are
prevented from expanding by the constricted mesodermal layer
(Fig. 3E,G)
(Mahlapuu et al., 2001b). The
yolk sac mesoderm in this mutant has abnormal adhesion properties, presumably
owing to ectopic co-expression of Vcam1 with its ligand, 
4-integrin,
throughout the extraembryonic mesoderm
(Mahlapuu et al., 2001b). The
visceral endoderm was seen to be lined on the inner surface with a thin layer
of endothelial (Pecam+ and Flk1+;
Fig. 3) cells, but the bulk of
the yolk sac mesoderm was detached and formed a thick layer between the amnion
and the yolk sac endoderm. The separation started in the mesometrial pole at
E8.5 and spread to the entire yolk sac by E9.5
(Fig. 3E,G,I,J). The prolific
and adhesive mesoderm of yolk sac and amnion sets the
Foxf1-/- mutant apart from the Shh-/-;
Ihh-/- mutant, in which the amnion appeared normal and the
yolk sac mesoderm was hypoplastic and reduced to a thin lining of the
endoderm.
|
|
). The Smo-/- embryos were
indistinguishable from Shh-/-; Ihh-/-
embryos and showed robust Foxf1 expression in the allantois
(Fig. 4C,D), as well as in the
primitive streak region (Fig.
4D). Hence, Foxf1 transcription in these tissues differs
from that in lateral and yolk sac mesoderm by being independent of hedgehog
signaling. Cryptic Dhh expression, as well as maternal hedgehogs, can
be dismissed as reasons for the persistent expression of Foxf1 in
Shh-/-; Ihh-/- double knockouts.
|
). The loss of yolk sac Foxf1 expression in
these mutants, together with the avascular extraembryonic phenotype of
Foxf1-/- embryos, fit a model in which Foxf1 is a
mesodermal target that mediates the role of hedgehogs in blood vessel
formation. However, the allantois is a highly vascularized tissue in which
Foxf1 expression is independent of Smo. We therefore asked
whether vasculogenesis would proceed normally in the absence of hedgehog
signaling in a tissue that expresses Foxf1, by analyzing allantoic
vascular development. Explants of wt allantoic buds spontaneously formed a
simple, but prolific, vascular plexus within 24 hours of culture, readily
identified by immunostaining for the endothelial marker Pecam
(Fig. 4E). Allantoic buds from
Smo-/- embryos formed extensive networks of endothelial
tubes, indistinguishable from those of wt explants
(Fig. 4F). This demonstrated
that formation of a vascular plexus can occur independently of hedgehog
signaling. Allantoic bud explants from Foxf1-/- embryos
contained Pecam+ cells, but these did not form vascular tube
networks (Fig. 6E). Taken
together, these results show that Foxf1 is an important component of
the vasculogenesis pathway and that Foxf1 expression requires
hedgehog signaling in some, but not all, tissues.
The vasculogenic activity of Foxf1 is mediated by Bmp4
Which target genes of Foxf1 mediate its vasculogenic activity? Several
observations suggest Bmp4 as a good candidate. Expression of
Bmp4 has been shown to be activated by Foxf proteins in some tissues
(Mahlapuu et al., 2001b;
Ormestad et al., 2006).
Furthermore, Bmp4 is known to be associated with blood vessel formation in
several systems (reviewed by Moser and
Patterson, 2005). Several predictions follow from the hypothesis
that Bmp4 is a key target of Foxf1 that induces vasculogenesis:
Bmp4 should be expressed at the sites and stages of active
vasculogenesis; it should exhibit reduced expression in avascular tissues of
the hedgehog and Foxf1 mutants; and the distinct vascular phenotypes
of Smo-/- and Foxf1-/- embryos should
be reflected in a corresponding difference in Bmp4 expression. A
Bmp4lacZ knock-in allele
(Lawson et al., 1999) allowed
visualization of Bmp4 transcription in thin tissues such as the yolk
sac and amnion. Embryos heterozygous for this allele had lacZ
staining in all extraembryonic mesoderm (yolk sac, amnion and allantois), the
primitive streak, the lateral plate mesoderm and the heart
(Fig. 4G,H and
Fig. 5A-E). In the
Smo-/- background, Bmp4lacZ expression
in yolk sac and lateral plate was reduced dramatically, but no significant
change was observed in the primitive streak or allantois
(Fig. 4I,J). In the
Foxf1-/- background, Bmp4lacZ
expression was similarly reduced in yolk sac and lateral plate and remained
high in the primitive streak. However, in contrast to
Smo-/-, the Foxf1 mutant embryos exhibited a
dramatic reduction of Bmp4lacZ expression in the allantois
(Fig. 5F-J). These results
suggest that Bmp4 expression during gastrulation is independent of
Foxf1, but as the cells move out of the primitive streak to form the lateral
or extraembryonic mesoderm, maintenance of Bmp4 transcription
requires Foxf1. A similar relationship appears to exist between Foxf1
and hedgehogs, because expression of Foxf1 in the primitive streak is
hedgehog-independent, but its persistence in lateral and yolk sac mesoderm
requires Smo and at least one of the ligands, Shh or Ihh. The exception is the
allantois, which retains Foxf1 and Bmp4 expression even in
the absence of hedgehog signaling.
|
The results presented here show that hedgehog signaling is dispensable for vascular tube formation in the allantois and suggest that this is accomplished by uncoupling Foxf1 - and thereby Bmp4 - expression from the hedgehog pathway. We next asked whether the same downstream mechanisms operate in a tissue where hedgehog signaling is essential for vascular development. In other words, can the requirement for hedgehogs be bypassed by the addition of Bmp4? We cultured yolk sac explants from Smo-/- embryos in vitro and supplemented the medium with Bmp4. Yolk sacs from E9.5 Smo-/- embryos were cut in half and the left- and right-hand sides cultured on separate permeable membranes. Bmp4 was added to one of the halves and after 24 hours of culture the explants were stained with the Pecam antibody. As shown in Fig. 6G,H, addition of Bmp4 led to formation of a well-developed plexus of endothelial tubes in spite of the absence of functional hedgehog signal transduction. This demonstrates that hedgehog signaling is dispensable for vasculogenesis in the yolk sac, as long as Bmp4 is present. It also proves that progenitors of endothelial cells are present, i.e. the Smo-/- yolk sac phenotype is not caused by a failure of progenitor cells to migrate and colonize the extraembryonic mesoderm.
|
).
Primitive hematopoietic cells (
-globin+) were aberrantly
present in the amnion and abundant in the mesometrial pole of the yolk sac,
but absent in the antimesometrial pole and in the allantois. Widespread
misexpression of the SMC marker -actin (SMA) was observed in yolk sac,
amnion and allantois (Mahlapuu et al.,
2001b). To investigate whether the excess of SMC progenitors was
accompanied by a decrease in angioblasts, and whether this ratio is controlled
by Bmp, we cultured Foxf1-/- allantoic explants in the
presence and absence of Bmp4 and stained for SMA and Flk1
(Fig. 7). Wild-type explants
had a moderate number of SMA+ cells loosely associated with the
Flk1+ endothelial tubes (Fig.
7A). Foxf1-/- explants contained
Flk1+ cells, but SMA+ cells were much more abundant and
widespread in Foxf1-/- explants than in wt
(Fig. 7B). Consistent with the
presence of definitive hematopoietic progenitors in allatoic buds
(Zeigler et al., 2006), a few
CD41+ cells (Mikkola et al.,
2003) were observed, but did not differ significantly in number
between the genotypes (see Fig. S3 in the supplementary material). Inclusion
of Bmp4 in the culture medium not only induced vascular formation, but also
significantly reduced the number of SMA+ cells
(Fig. 7C). Thus, Bmp can
reverse the abnormal accumulation of SMA+ cells that results from
inactivation of Foxf1 and normalize the SMC/angioblast ratio. This
might reflect an ability of Bmp signaling to influence fate decisions in the
extraembryonic mesoderm, or to inhibit proliferation of SMC progenitors. |
DISCUSSION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The described pathway simplifies the interpretation of several observations
that have troubled previously suggested models of direct, cell-autonomous
involvement of hedgehog in vascular tube formation. For example,
Smo-/- mutants have absent or severely defective dorsal
aortae along much of the embryo, but towards the posterior end the morphology
of these blood vessels improves to near normal
(Vokes et al., 2004;
Zhang et al., 2001).
Inactivation of Smo abrogates all hedgehog signaling, which makes
this gradient in vascular development difficult to reconcile with hedgehog
being required for endothelial tube formation by acting directly on
angioblasts. This prompted speculation of alternative pathways, both
hedgehog-dependent and -independent, acting in different parts of the embryo
(Byrd and Grabel, 2004;
Vokes et al., 2004). The high
level of hedgehog-independent Bmp4 expression in the primitive streak
area generates a localized, posterior source of Bmp4 in
Smo-/- embryos, which readily explains the observed
gradient in dorsal aorta development. In contrast to hedgehog signaling, which
is completely blocked in Smo-/- mutants, Bmp4 expression
is only reduced. Variation, stochastic or genetic, in the residual amounts of
Bmp will inevitably give rise to interindividual phenotypic variation. This is
seen, for example, in the development of Smo-/- embryonic
vasculature (Vokes et al.,
2004) and in the yolk sac of Smo-/- embryos,
which often have patches of rudimentary plexus formation in the area closest
to the embryo (Byrd et al.,
2002).
|
|
). This
is consistent with the robust growth of Foxf1-/- allantoic
explants in vitro and implies that the failure to form a vascular plexus is
not a consequence of a general hypoplasia. In other systems, Bmps have been
shown to increase Vegf expression and stimulate proliferation of
Flk1+ cells (Deckers et al.,
2002; He and Chen,
2005; Nimmagadda et al.,
2005; Reese et al.,
2004). It is therefore likely that Bmp acts through the Vegf
pathway also in extraembryonic vasculogenesis.
Why does the allantois differ from other extraembryonic mesodermal
structures with regard to activation of Foxf1? In fish and
amphibians, vasculogenesis and hematopoiesis are initiated in ventral
mesoderm. A vascular bed encloses yolk contained in the primitive gut and both
hedgehog, expressed in the endoderm, and BMP4, expressed in the ventral
mesoderm, are important for its formation
(Brown et al., 2000;
Harland, 1994). As an
adaptation to terrestrial development, the endoderm-mesoderm bilayer of
oviparous amniotes folds into three distinct compartments - the gut, the yolk
sac and the allantois - all with the same basic organization and with
vasculogenesis occurring throughout. The selective forces that shaped these
extraembryonic structures are absent in placental mammals. Owing to
phylogenetic constraints, the structures are still part of mammalian
embryology, but have lost their original functions and in some cases acquired
novel ones. In consequence, they display a remarkable morphological diversity
across mammalian species. The murine allantois represents an evolutionary
oddity that has lost the endodermal component and thus the source of hedgehog.
This would arrest vasculogenesis, unless replaced by autocrine hedgehog
signaling in the mesoderm, or by other means of activating the key mesodermal
targets. In mouse, this problem appears to have been solved by
hedgehog-independent transcriptional activation of the Foxf1
gene.
|
). Shh mRNA is present in the yolk sac endoderm,
but at a low level that has been assumed to be without physiological relevance
(Farrington et al., 1997). The
phenotypes of Shh-/-; Ihh-/- and
Smo mutants were indistinguishable and differed strikingly from both
hedgehog single nulls. This demonstrates a widespread redundancy between
Shh and Ihh. Specifically, our results show that Shh
contributes to yolk sac vascular development, but does not support the notion
of a role for Dhh in this process. It should be emphasized that the main
argument for dismissal of Dhh is not the absence of detectable expression, but
the identical phenotypes (including allantoic vasculogenesis) of
Smo-/- and Shh-/-;
Ihh-/-.
Bmp4 expression during gastrulation does not require Foxf1.
However, once mesodermal cells exit from the primitive streak and reach the
lateral plate or extraembryonic structures, Foxf1 becomes essential for
maintaining high-level Bmp4 transcription. Injection of BMP4
mRNA in 8-cell Xenopus embryos induced transcription of
FoxF1 in gastrula stage animal caps
(Tseng et al., 2004). This is
consistent with the onset of expression being earlier for Bmp4 than
Foxf1. Hence, during gastrulation, FoxF1 expression in
nascent mesoderm appears to require Bmp, whereas later on the relationship is
reversed. Interestingly, a similar relationship has been described in
Drosophila where Dpp (the Bmp homolog) is required for activation of
biniou (the Foxf homolog) early in development in the trunk
visceral mesoderm primordium, but Biniou activates dpp at later
stages in the visceral mesoderm (Zaffran
et al., 2001).
The activation of FoxF1 by BMP4 in early Xenopus embryos
(Tseng et al., 2004) contrasts
with the inhibition of Foxf1 in murine lung mesenchyme by Bmp4 from
the distal lung bud epithelium (Mahlapuu
et al., 2001a). The epithelio-mesenchymal cross-talk during lung
branching morphogenesis is complex and it is unclear whether the effect on
Foxf1 is direct or indirect. In the early embryo, where
Foxf1 and Bmp4 are co-expressed in the mesoderm, there is no
evidence for feedback inhibition.
Supplementary material
Supplementary material for this article is available at
http://dev.biologists.org/cgi/content/full/134/20/4432/DC1
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ACKNOWLEDGMENTS |
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