1 Department of Biochemistry and Molecular Biology, Norris Cancer Hospital, Keck
School of Medicine, University of Southern California, 1441 Eastlake Avenue,
Los Angeles, CA 90089, USA
2 Center for Craniofacial Molecular Biology, School of Dentistry, University of
Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033,
USA
* Author for correspondence (e-mail: maxson{at}hsc.usc.edu)
Accepted 2 September 2005
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SUMMARY |
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Key words: Neural Crest, Calvaria, Craniofacial, Cranial Ganglia, Cardiac outflow tract, Msx1, Msx2, Mouse embryo
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Introduction |
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Combined human-genetic and molecular approaches have uncovered several
genes required for neural crest development in humans and mice. These include
transcription factors, cell adhesion molecules and molecules involved in
cell-cell signaling (Wilkie and
Morriss-Kay, 2001; Gammill and
Bronner-Fraser, 2003
; Halloran
and Berndt, 2003
; Santagati
and Rijli, 2003
). Most of the major signaling pathways, including
Bmp, Wnt, Fgf, Shh, RA (retinoic acid) and ET (endothelin), have roles in
neural crest development. Although these roles are increasingly well
understood (Knecht and Bronner-Fraser,
2002
; Gammill and
Bronner-Fraser, 2003
), it remains unclear how neural crest cells
respond to and integrate signals from these pathways. One approach to this
problem is to investigate the functions and interactions of the transcription
factors that mediate the signals from these various pathways. Here, we focus
on the Msx genes effectors of Bmp, Wnt and Fgf signaling and
their roles in the development of subpopulations of neural crest that
contribute to the craniofacial apparatus, cranial nerves, and cardiac outflow
septum.
Msx genes form a subfamily within the Nk-like homeobox gene family
(Gauchat et al., 2000;
Pollard and Holland, 2000
).
Mammals possess three Msx genes, Msx1, Msx2 and Msx3
(Davidson, 1995
;
Shimeld et al., 1996
;
Wang et al., 1996
). In
vertebrates, Msx1 and Msx2 are known to act in a variety of
cell types to control cell proliferation, differentiation
(Woloshin et al., 1995
;
Liu et al., 1999
;
Odelberg et al., 2000
;
Hu et al., 2001
;
Han et al., 2003
;
Ishii et al., 2003
) and
survival (Marazzi et al.,
1997
). From work in several vertebrate embryos and various organ
systems, it has been shown that Msx genes function as downstream effectors of
the Bmp pathway (Vainio et al.,
1993
; Marazzi et al.,
1997
; Bei and Maas,
1998
; Hollnagel et al.,
1999
; Sirard et al.,
2000
; Daluiski et al.,
2001
; Bruggger et al., 2004). In addition, in some tissues, they
serve as effectors of the Wnt and Fgf pathways
(Chen et al., 1996
;
Montero et al., 2001
;
Willert et al., 2002
;
Hussein et al., 2003
).
Msx1 and Msx2 are expressed in premigratory and migratory
neural crest, as well as in the neural crest-derived mesenchyme of the
pharyngeal arches and median nasal process
(Davidson, 1995
;
Bendall and Abate-Shen, 2000
;
Maxson et al., 2003
). Recent
studies in Xenopus and chicken showed that the forced expression of
Msx1 can induce neural crest marker expression in the dorsal aspect
of embryos (Tribulo et al.,
2003
; Liu et al.,
2004
).
Mice homozygous for a targeted mutation in Msx1 exhibit agenesis
of the teeth, a cleft palate, and abnormalities of the cranial skeleton
(Satokata and Maas, 1994).
Tissue recombination experiments have shown that Msx1 plays an
essential role in epithelial-mesenchymal interactions during the tooth
development (Chen et al.,
1996
; Bei and Maas,
1998
). Han et al. provided evidence that Msx1 also
controls cell proliferation in the dental mesenchyme
(Han et al., 2003
). A defect
in the development of the frontal bone is evident in mice homozygous for a
targeted mutation in Msx2, mimicking key features of Familial
Parietal Foramina (Satokata et al.,
2000
). We showed recently that the cause of this frontal bone
defect includes deficiencies in the differentiation and proliferation of
neural crest-derived calvarial osteogenic cells
(Ishii et al., 2003
). Mice
with homozygous mutations in both Msx1 and Msx2 die in late
gestation with severe craniofacial malformations, including exencephaly, cleft
palate, agenesis of teeth, and unossified calvarial bones
(Bei and Maas, 1998
;
Satokata et al., 2000
).
Although this spectrum of anomalies in Msx1/2 mutants
suggests a deficiency in the cranial neural crest, an analysis of neural crest
development in such embryos has been lacking. Here, we report that
Msx1/;
Msx2/ embryos have defects not previously
described in derivatives of the craniofacial and cardiac neural crest. These
include hypoplasia and mis-patterning of the cranial ganglia, and anomalies in
the conotruncus of the heart. The expression of neural crest markers in
Msx1/2 mutants revealed a delay in the migration of neural
crest cells originating in r2, r4 and r6-r8. There was, in addition, a
disorganization of the neural crest cells forming cranial ganglia, and a
mixing of some subpopulations of neural crest, suggesting defects in neural
crest compartment boundaries. Hindbrain marker gene expression suggested that
Msx1/2 might affect rhombomere development. Finally, although the
proliferation of neural crest-derived mesenchyme was unchanged in
Msx1/2 mutants, the number of apoptotic cells was elevated
substantially in neural crest populations that contribute to the cranial
ganglia and the first pharyngeal arch. These results suggest that
Msx1/2 act at several different steps of neural crest
development, and in different neural crest subpopulations, to control the
patterning of the craniofacial apparatus and cardiac outflow tract.
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Materials and methods |
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Immunostaining, analysis of skeletal morphology and detection of apoptotic cells
Whole-mount immunohistochemistry was carried out according to Mark et al.
(Mark et al., 1993), using the
2H3 anti-neurofilament monoclonal antibody (1:500, Developmental Studies
Hybridoma Bank). Primary antibody was followed by HRP-conjugated goat
anti-mouse IgG antibody (1:100, Calbiochem). 4-chloro-1-naphtol chromogenic
substrate (Sigma) was used for signal detection. Whole heads of E15.5 embryos
were stained in PBS containing 1 µg/ml DAPI for 30 minutes and photographed
under UV light. Detection of alkaline phosphatase and counterstaining with
Nuclear Fast Red were as described (Liu et
al., 1999
). Whole-mount analysis of skeletal morphology was
performed as described by McLeod (McLeod,
1980
) and Hogan et al. (Hogan
et al., 1994
). For TUNEL identification of apoptotic cells,
embryos were fixed in 4% paraformaldehyde and cryosectioned (10 µm). The In
Situ Cell Death Detection Kit (Roche) was used according to the manufacturer's
instructions. Sections were then treated with anti-phosphorylated Histone H3
polyclonal antibody (1/100, Upstate). then incubated with rhodamine-conjugated
anti-rabbit IgG (1/100, Molecular Probes). Nuclei were counter-stained with
DAPI. After Prolong (Molecular Probes) mounting, signals were photographed
under fluorescence. Cell death was detected in whole embryos by Nile blue
sulfate (Sigma), as described (Trumpp et
al., 1999
).
In situ hybridization
Whole-mount in situ hybridization was performed according to Hogan et al.
(Hogan et al., 1994).
Conclusions were based on at least two independent experiments.
Digoxigenin-labeled anti-sense RNA probes were visualized by BM-purple
substrate (Roche). An Msx1 1.2 kb XhoI-XbaI cDNA
fragment was subcloned into pSP72. An RNA probe was synthesized from the T7
promoter. Other RNA probes were generated as reported previously:
Ap-2
(Mitchell et al.,
1991
), Bmp4 (Wu et
al., 2003
), cdh6
(Inoue et al., 1997
),
Crabp1 (Stoner and Gudas,
1989
), Dlx5 (Depew et
al., 1999
), Fgf8
(Crossley and Martin, 1995
),
Epha4 (Nieto et al.,
1992
), Hoxb1, Hoxd4
(Jiang et al., 2002
),
Krox20 (Wilkinson et al.,
1989
), Msx2, Twist
(Ishii et al., 2003
),
Sox10 (Kuhlbrodt et al.,
1998
), Tbx1 (Bollag et
al., 1994
) and Wnt1
(Parr et al., 1993
).
Wnt1-Cre/R26R reporter assay
Msx1 and Msx2 mutants were crossed with Wnt1-Cre
or R26R lines, producing embryos with the genotype
Msx1/;
Msx2/;
Wnt1-Cre/+; R26R/+. ß-Galactosidase analysis was
carried out as described (Chai et al.,
2000; Jiang et al.,
2000
).
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Results |
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Afferent neurons and glial cells of the cranial and dorsal root ganglia are
derived from the neural crest (Le Douarin
and Kalcheim, 1999; Barlow,
2002
). To examine the development of the cranial and dorsal root
ganglia in Msx1/2 null embryos, we performed whole-mount
immunohistochemistry on E10.5 embryos using an anti-neurofilament antibody
(Fig. 2). In all mutant embryos
examined (n=4), the oculomotor nerve (III) was absent or disrupted,
and the trigeminal ganglion (V) was significantly reduced in size
(Fig. 2B-D). These data show
that loss of Msx1/2 resulted in hypoplasia and mispatterning
of the cranial ganglia. The dorsal root ganglia, by contrast, were
indistinguishable from wild type (data not shown). The proximal part of the
IXth nerve was missing, and the distal portion of the IXth nerve was fused
with the Xth nerve. An abnormal connection between the trigeminal and
facial-acoustic nerves (VII-VIII) was evident in two embryos
(Fig. 2B,C). The fusion of the
IXth and Xth nerve was less dramatic in
Msx1/;
Msx2+/ and in
Msx1+/;
Msx2/ embryos
than in Msx1/;
Msx2/ embryos
(Fig. 2E,F, data not shown),
suggesting that patterning defects of the cranial nerve are Msx gene-dosage
dependent.
Cardiac neural crest cells contribute to the cardiac outflow septum, and
are required for the proper alignment of the aorta and pulmonary trunk
(Kirby and Waldo, 1995).
Although neither Msx1 nor Msx2 individual mutant mice
exhibit defects in the development of the cardiac outflow tract
(Kwang et al., 2002
), all
Msx1/2 null mice that we examined (n=4) had
conotruncal abnormalities, including double outlet right ventricle (DORV),
Tetralogy of Fallot and persistent truncus arteriousus (PTA)
(Fig. 3, data not shown). Each
of these defects is attributable to defective neural crest development
(Kirby and Waldo, 1995
). In
addition, double-mutant mice exhibited ventricular-septal defects (VSDs),
hypoplastic valves, and dysmorphogenesis of the ventricular wall and
myocardium (these defects will be described in detail elsewhere). Mutant
hearts also contracted irregularly (data not shown), which, together with the
finding of generalized edema, suggested that Msx1/2 null mutants had
cardiac insufficiency. We did not detect conotruncal abnormalities in
Msx1/;
Msx2+/ or
Msx1+/;
Msx2/ embryos
(data not shown).
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Each of these markers was expressed normally in the first and second arches
(Fig. 4A-F), suggesting that
the anomalies in neural crest-derived structures in the pharyngeal arches of
Msx1/2 mutants are not a result of large-scale deficiencies
in the distribution of neural crest. Use of the
Wnt1-Cre/R26R system
(Chai et al., 2000;
Jiang et al., 2000
) to mark
neural crest in Msx1/2 mutants confirmed these findings
(Fig. 4G,H).
Delayed migration, mispatterning and inappropriate mixing of subpopulations of neural crest in Msx1/2 mutant embryos
To determine whether more subtle changes in the specification or
distribution of subpopulations of neural crest are responsible for the
observed morphological defects, we examined the expression of marker genes at
several stages of neural crest development (Figs
4,
5,
6,
7,
8). We used
Ap-2 to assess neural crest development at E8.5.
Ap-2
is normally expressed in crest cells in the neural folds
and in migratory neural crest cells
(Mitchell et al., 1991
)
(Fig. 4I,M).
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To assess neural crest development in embryos subsequent to E8.5, we
continued to use Ap-2 (Figs
5,
6). We also used cdh6
and Sox10, which are expressed in neural crest cells as they emigrate
from the neural tube (Inoue et al.,
1997
; Southard-Smith et al.,
1998
).
At E9.5, Msx1 and Msx2 are expressed in the dorsal neural
tube (Davidson, 1995)
(Fig. 5A,B). Consistent with
previous descriptions, Ap-2
, cdh6 and Sox10
were expressed in streams of neural crest migrating from r2 and r4 in the
preotic hindbrain, and from r6-r8 in the postotic neural tube
(Mitchell et al., 1991
;
Inoue et al., 1997
;
Southard-Smith et al., 1998
)
(Fig. 5C,E,G,I,K;
Fig. 6A,C,E,G,I,K,M,O). Ap-2
, cdh6 and Sox10 expression was not
detectable in r3 or r5, or in adjacent migratory crest cells
(Fig. 5M,O, data not
shown).
Differences in the expression of each of these three markers were evident
in Msx1/2 mutant embryos. Ap-2,
cdh6 and Sox10 were expressed ectopically in strips of cells
located in normally neural crest-free areas adjacent to r3 (arrowhead in
Fig. 5D,H,J,L;
Fig. 6B,F,H,N). Cross sections
showed that for all three markers this expression was in mesenchyme
(Fig. 5M-P, data not shown).
These data suggest that, in Msx1/2 mutants, neural crest
cells were located abnormally in areas adjacent to r3.
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Altered expression of Krox20 and Epha4 but normal expression of Hoxb1 and Hoxd4 in hindbrains of Msx1/2 mutant embryos
Changes in marker gene expression in cranial and cardiac neural crest
populations raised the issue of whether loss of Msx1 and
Msx2 affected rhombomere identity. We examined the expression of the
hindbrain markers, Krox20, Hoxb1, Hoxd4, Epha4 and Crabp1
(Fig. 7). Krox20 is
expressed in r3 and r5 (Sham et al.,
1993; Swiatek and Gridley,
1993
). Hoxb1 is expressed in r4
(Murphy et al., 1989
),
Hoxd4 in the neural tube from r7 caudally
(Morrison et al., 1997
), and
Epha4 in r3 and r5 (Nieto et al.,
1992
). Gain- and loss-of-function experiments have shown that
Krox20, Hoxb1, Hoxd4 and Epha4 are crucial for the
establishment of rhombomere identity
(Trainor and Krumlauf, 2000
).
Crabp1 is expressed in r2 and throughout the hindbrain, from r4 to r6
(Maden et al., 1992
).
Whole-mount stains with riboprobes for each of these markers revealed that Krox20 was expressed normally in r3 in E8.5 mutants, but exhibited a restriction in the caudal limit of its expression in r5 (Fig. 7B,D). By E9.5, the r5 expression of Krox20 was indistinguishable from that of wild type (Fig. 7F). The domains of expression of Hoxb1, Hoxd4 and Crabp1 were not altered in Msx1/2 mutant embryos at E9.0 or E9.5 (Fig. 7H,J,L, data not shown). Intriguingly, however, Epha4 expression was increased significantly in r3, and was expanded anteriorly into r1 and r2 (Fig. 7N,P). That hindbrain marker gene expression was unchanged in r4, r6 and r7 suggests that the defects in neural crest populations derived from these rhombomeres result from events downstream of the establishment of rhombomere identity. The changes in Krox20 and Epha4 expression suggest, however, that loss of Msx1 and Msx2 may at least transiently influence the development of r1, r2, r3 and r5.
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Increased apoptosis but unchanged proliferation in subpopulations of cranial neural crest in Msx1/; Msx2/ embryos
We next assessed apoptosis and proliferation in Msx1/2
double-mutant embryos. Apoptosis was detected by a TUNEL assay, and
proliferation by an antibody against 10-phosphorylated histone H3, which marks
cells in M phase. These assays were carried out on the same cross sections of
embryos. At E9.5, an increase in TUNEL-positive cells relative to controls was
evident in the posterior prominence of the optic vesicle, as well as in the
maxillary and mandibular prominences of the first pharyngeal arch
(Fig. 9B,D,F). The majority of
mesenchymal cells at these sites are derived from the cranial neural crest
(Chai et al., 2000;
Jiang et al., 2000
).
Whole-mount Nile Blue staining, which marks dying cells, confirmed these
results (Fig. 9G-L).
Concentrations of Nile Blue-positive cells were evident (1) in the area of the
trigeminal ganglion (Fig. 9H,
arrow), and (2) in the proximal (open arrowheads in
Fig. 9H) and distal portions
(arrowhead in Fig. 9H,J) of the
first pharyngeal arch. No changes in TUNEL or Nile Blue staining were evident
in the hindbrain or in migrating postotic neural crest cells (including
cardiac neural crest) of Msx1/2 mutants at E9.5
(Fig. 9J,L, data not
shown).
We did not detect significant differences in the percentage of cells stained for phosphorylated histone H3 or BrdU in the pharyngeal arches or trigeminal ganglia (Fig. 9; data not shown). Consistent with the apparent lack of change in cell proliferation, counts of cell densities in the first pharyngeal arch showed no significant differences between Msx1/2 mutants and control embryos (Fig. 9, data not shown). These results suggest that the combined loss of Msx1 and Msx2 influenced the survival but not the proliferation of subpopulations of neural crest-derived mesenchyme in the craniofacial region.
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Discussion |
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Our results show that loss of Msx1/2 results in the
delayed appearance outside the neural tube of cells expressing neural crest
markers. This is first evident in the expression of Ap-2 at
E9.0, and is apparent at later stages in the expression of cdh6 and
Sox10. Whether this delay is due to a deficiency in the production,
delamination or migration of neural crest cells remains unclear. A second
intriguing anomaly is the partial merging or mixing of crest populations.
Apparent in the expression patterns of Ap-2
, cdh6 and
Sox10, such mixing occurred between crest cells emigrating from r2
and those emigrating from r4, as well as between streams of crest emerging
from the postotic rhombomeres 6, 7 and 8 (Figs
5,
6). DiI labeling will address
the origin and migratory path of aberrant neural crest at the level of r3.
Krox20, kreisler (Mafb Mouse Genome Informatics), and the
combinatorial actions of Hox family members, establish and maintain boundaries
between rhombomeres and between subpopulations of migrating neural crest
cells. They do so, at least in part, by controlling the activities of Epha4
and Epha7 (Trainor and Krumlauf,
2000), which control cell-cell affinity. Reduced Krox20
expression in r5 and increased Epha4 from r1 to r3 of
Msx1/2 mutants suggests that Msx1/2 may
participate in rhombomere development. In normal embryos, neural crest is
excluded from r3, whereas in Msx1/2 mutants it is not.
Upregulation of Epha4 in Msx1/2 mutants may have some part in
abrogating this exclusion. It is intriguing that in Xenopus, forced
expression of a dominant-negative form of Epha4 disrupted neural
crest segregation (Smith et al.,
1997
). Overexpression of Epha4 in
Msx1/2 mutants may have a dominant-negative effect and, as a
consequence, may inhibit neural crest boundary formation between r2 and
r4.
We consistently observed aberrant Ap-2 expression in the
dorsal midline of Msx1/2 mutant hindbrain from E9.0 through
E10.5 (Fig. 5, data not shown).
This may reflect a defect in the specification of a subpopulation of neural
crest cells. Msx1 and Msx2, as well as Ap-2
can maintain cells in an undifferentiated state
(Liu et al., 1999
;
Odelberg et al., 2000
;
Hu et al., 2001
;
Pfisterer et al., 2002
). That
these three genes have similar functions, and that each is regulated by both
Bmp and Wnt signals (Vainio et al.,
1993
; Willert et al.,
2002
; Luo et al.,
2003
), suggest that they may participate in a common molecular
cascade in neural crest development. Also supporting this hypothesis is the
striking similarity of phenotypes caused by the loss of
Msx1/2 and Ap-2
. Both mutants, for example,
exhibit exencephaly, craniofacial skeletal defects, hypoplastic cranial
ganglia, persistant truncus arteriosus and thoraco-abdominoschisis (open body
wall) (Schorle et al., 1996
;
Zhang et al., 1996
;
Brewer et al., 2002
). In
Ap-2
mutants, as in Msx1/2 mutants, increases in the
apoptosis of neural crest cells are likely to contribute to at least some
defects in neural crest-derived structures
(Schorle et al., 1996
).
Msx1/2 are required for survival of neural crest subpopulations
Our results suggest that apoptosis may contribute to some of the
morphological deficiencies of Msx1/2 mutant embryos. The
reduction in size of the trigeminal ganglion, as shown by decreased
neurofilament expression, is preceded by a reduction of neural crest marker
expression and a substantial increase in the number of apoptotic cells
relative to control embryos (Fig.
9). Similarly, numbers of apoptotic cells are elevated in the
maxillary prominence at E9.5. The mechanisms underlying this increase,
including the issue of whether it is cell autonomous, remain unknown.
Previous work has shown that forced expression of Msx2 can cause
apoptosis in P19 cells and in the hindbrain of the chick embryo
(Marazzi et al., 1997;
Takahashi et al., 1998
). A
prediction of these overexpression experiments is that loss of
Msx1/2 should reduce apoptosis, which does not appear to be
the case, either in the hindbrain or the pharyngeal arches. Although it is
difficult to reconcile these results with ours, it is possible that the forced
expression of Msx genes has a dominant-negative effect. Alternatively, the
function of Msx genes may differ in cultured cells compared with in embryos,
or in the chicken versus the mouse.
Msx genes and pharyngeal arch development
We are intrigued by the finding that loss of Msx1/2
function results in fusion of the maxillary and mandibular prominences, as
well as in the reduced growth of these structures. Recent studies have shown
that patterning of the craniofacial skeleton is controlled, in part, by
non-Hox homeobox genes, including members of the Otx and Dlx families
(Matsuo et al., 1995;
Kuratani et al., 1997
;
Depew et al., 2002
;
Robledo et al., 2002
). Because
Msx1 and Msx2 are highly expressed in the maxillary
prominence and mandibular arch, they could, in principle, function with other
non-Hox homeobox genes in the axial patterning of craniofacial structures. In
contradistinction to Dlx5/Dlx6 knockout embryos, which
exhibit a homeotic phenotype (Depew et
al., 2002
; Robledo et al.,
2002
), Msx1/2 mutant embryos do not show
evidence of homeotic transformations of craniofacial features. Although we
have not systematically surveyed the expression of non-Hox homeobox genes in
Msx1/2 mutants, we have examined the expression of
Dlx5, which is unaltered. This is consistent with the view that, in
jaw development, the actions of Msx1/2 either parallel that
of Dlx5 or are downstream of it. To the extent that a general
function for Msx genes can be inferred from our data, such a function seems
more likely to include the local control of cell segregation, differentiation
and survival, than broad effects on region specification.
Role of Msx1/2 in the developing heart
Neither the loss of Msx1 nor Msx2 individually causes
outflow tract defects (Kwang et al.,
2002). However, our results show that the combined loss of
Msx1 and Msx2 results in major defects in the outflow tract
in a high percentage of embryos. We did not detect significant changes in the
expression of Fgf8 or Tbx1, which function in the pharyngeal
endoderm in signaling processes that influence cardiac crest development
(Vitelli and Baldini, 2003
).
Similarly, the patterning of the caudal hindbrain from which the cardiac
neural crest originates appeared to be largely normal in
Msx1/2 mutants, as assessed by the expression of
Hoxd4 and Crabp1. These results are consistent with our
observation that cardiac neural crest cells are present in the pharyngeal
arteries at E9.5 (Fig. 6). It
will be interesting to determine whether these defects are caused by anomalies
in the secondary heart field (Waldo et
al., 2001
), and whether they are crest-cell autonomous.
Interaction between signaling pathways and Msx genes
Several upstream regulators of Msx genes have been identified. These
include Bmps, Wnt/ß-catenin and Fgf pathways. Msx1/2
mutant embryos share features with mutants in each of these pathways
(Ohnemus et al., 2002;
Dâelot et al., 2003
;
Stottmann et al., 2004
;
Ikeya et al., 1997
;
Kioussi et al., 2002
;
Abu-Issa et al., 2002
;
Frank et al., 2002
). The
involvement of Msx1/2 in multiple aspects of neural crest
cell development implies that, depending on stage and tissue, Msx genes may
function to integrate signals from several pathways.
Our results showed that Bmp4 expression is increased in the cranial neural crest and pharyngeal arches of Msx1/2 mutant embryos. This suggests that Msx genes negatively control Bmp signals in these structures. Although, Msx genes do not appear to control the expression of Wnt1 and Fgf8 in neural crest development, it remains possible that there are additional signaling molecules regulated by Msx genes.
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ACKNOWLEDGMENTS |
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