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First published online June 6, 2008
doi: 10.1242/10.1242/dev.021170
1 Department of Biology, Case Western Reserve University, Cleveland, OH 44106,
USA.
2 Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892,
USA.
3 Department of Genetics, Case Western Reserve University, Cleveland, OH 44106,
USA.
4 Department of Dermatology, Case Western Reserve University, Cleveland, OH
44106, USA.
* Author for correspondence (e-mail: rpa5{at}case.edu)
Accepted 10 May 2008
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MATERIALS AND METHODS
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DISCUSSION
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Key words: Dermis, Cell fate, Cell survival, Skin, Sternum
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INTRODUCTION |
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MATERIALS AND METHODS
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;
Supp and Boyce, 2005).
Craniofacial, dorsal trunk and ventral trunk dermis originate from different
multipotential progenitor populations
(Couly et al., 1992;
Mauger, 1972), but is the
signaling mechanism for mammalian dermal cell fate selection conserved or
divergent in these different populations?
The skin consists of the epidermis, derived from the surface ectoderm, and
the underlying dermis. Reciprocal interactions between the surface ectoderm
and dermis induce the development of the epidermal appendages, such as hair
follicles and glands of the skin (Millar,
2002). Dermal fibroblasts from different parts of the embryo have
distinct inductive properties (Foley et
al., 2001; Hardy,
1992; Miletich and Sharpe,
2004) and maintain positional identity in adult humans
(Chang et al., 2002). Diverse
origins of the dermis might be the source of variation in skin patterning,
pigmentation color, and types of epidermal appendages that are found on the
body (Candille et al., 2004).
The genetic program to establish the distinctiveness of dermal cells in
different parts of the mammalian embryo is yet to be discovered.
To address the underlying basis for differences in dorsal versus ventral
skin patterning, studies have been carried out in the chick embryo, and these
implicate different signaling molecules that are important for ventral dermal
cell development (Fliniaux et al.,
2004a; Fliniaux et al.,
2004b; Sengel and Kieny,
1967). Fate-mapping studies in the chick embryo demonstrate that
the proximal part of the somatopluere closest to the somites gives rise to the
feather-forming dermis in the ventral trunk
(Fliniaux et al., 2004a;
Mauger, 1972). Suppression of
bone morphogenetic protein (BMP) signaling by endogenous Noggin expression or
ectopic expression of Sonic Hedgehog can induce the differentiation of ventral
trunk dermal progenitors into feather-forming dermis
(Fliniaux et al., 2004a). Early
during lateral plate mesoderm (LPM) cell differentiation in the chick embryo,
Wnts are expressed in the ectoderm overlying the somatopleure
(Fliniaux et al., 2004a;
Rodriguez-Niedenfuhr et al.,
2003; Schubert et al.,
2002). The requirement of any signaling molecule in ventral dermal
cell development has not been determined in either the chick or the mammalian
embryo. In this study, we examine the role of Wnt signaling in ventral dermal
cell development.
The canonical Wnt signaling pathway is involved in early embryonic
patterning, cell fate specification, proliferation, and the maintenance of
stem cell compartments (Nelson and Nusse,
2004). β-Catenin is a key transducer of the Wnt signaling
pathway (Nelson and Nusse,
2004). Embryos fail to gastrulate in the absence of β-catenin
activity (Haegel et al.,
1995), and unregulated β-catenin activity leads to cancer in
adults (Giles et al., 2003).
In the absence of Wnt signaling, the β-catenin protein is phosphorylated
and marked for degradation (Nelson and
Nusse, 2004). In the presence of Wnt signaling, the
unphosphorylated form of β-catenin accumulates in the cytoplasm,
translocates to the nucleus, binds to the TCF/Lef family of transcription
factors, and promotes the transcription of Wnt target genes
(Brantjes et al., 2002).
Changes in downstream target gene expression mediate the diverse roles of Wnt
signaling in development and disease
(Nelson and Nusse, 2004;
Sancho et al., 2003).
Studies in the chick embryo demonstrate the requirement of Wnt signaling in
early dorsal dermal cell development from the dermamyotome
(Olivera-Martinez et al.,
2002; Olivera-Martinez et al.,
2004). Our previous studies in the mouse embryo on dorsal dermal
fate specification from the central somite indicate that Wnts, via
β-catenin, provide an instructive signal for dermal fate
(Atit et al., 2006). Prior to
and during dorsal and ventral dermal cell specification in the mouse and chick
embryo, members of the Wnt family are expressed in the entire dorsal surface
ectoderm (Cauthen et al., 2001;
Parr et al., 1993;
Rodriguez-Niedenfuhr et al.,
2003; Schubert et al.,
2002). Using a transgenic Wnt signaling reporter, we now show that
Wnt signaling is transduced in ventral subectodermal cells, which include
dermal progenitors. The role of Wnt signaling in the specification and
development of the ventral dermis in the mouse or chick embryo is unknown
(Fuchs and Raghavan, 2002;
Millar, 2002;
Millar, 2005). In this study,
we have used two different mouse conditional mutants to identify the role(s)
of the Wnt signaling pathway in the development of the ventral trunk dermal
cells.
Here, we identify multiple roles for Wnt signaling/β-catenin in ventral dermal development. First, Wnt signaling/β-catenin is required for survival of the early dermal progenitors in the LPM. Later in development, Wnt signaling/β-catenin is necessary and sufficient for the specification of ventral dermal progenitors that are derived from the flank and ventral subectodermal mesenchyme. In the conditional absence of Wnt signaling/β-catenin, the ventral dermis fails to develop. Our studies on ventral dermal development reveal a new role for Wnt signaling/β-catenin in cell survival, and a conserved role in dermal cell specification.
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MATERIALS AND METHODS
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DISCUSSION
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) (obtained from Daniel Dufort). HoxB6Cre
(Lowe et al., 2000) and
En1Cre mice (Kimmel et al.,
2000) (obtained from Michael Keuhn and Alexandra Joyner,
respectively) were crossed to R26R mice (purchased from Jackson
Laboratories) to determine the efficiency of Cre-mediated recombination
(Soriano, 1999). To temporally
restrict the recombination of R26R, HoxB6Cre-ERT1
(obtained from Susan Mackem) and En1Cre-ERT1
(Sgaier et al., 2005)
(obtained from Alexandra Joyner) mice were used. Tamoxifen was administered by
intraperitoneal (IP) injection (1 mg/40 g mouse) of pregnant females carrying
E7.5 HoxB6Cre-ERT1; R26R embryos. Females
carrying E10.5 En1Cre-ERT1; R26R embryos were
given 3 mg/40 g of Tamoxifen by gavage. For deletion of β-catenin in the
ventral dermal progenitors, HoxB6Cre; R26R or En1Cre;
R26R mice were crossed with mice carrying an exon 2-6 floxed allele
of β-catenin (β-catlof)
(Brault et al., 2001)
(purchased from Jackson Laboratories). For activation of β-catenin in
ventral dermal progenitors, En1Cre; R26R mice were crossed
with mice carrying an exon 3 floxed allele of β-catenin
(β-catgof)
(Harada et al., 1999)
(obtained from Makoto M. Taketo). To determine the efficiency of Wnt pathway
activation and inactivation, TCF/Lef-lacZ; En1Cre mice were crossed
with β-catlof or β-catgof
mice. All the mice and embryos were genotyped as previously described. For
each experiment, five to eight embryos from two to three litters were
analyzed. All mouse experiments were done according to protocols approved by
the Case Western Reserve University IACUC committee.
In situ hybridization, immunohistochemistry and histology
Tissue preparation, histology, immunohistochemistry, lacZ
expression, and in situ hybridization with digoxigenin-labeled probes were
performed as previously described (Atit et
al., 2006). The Dermo1 probe was a gift from Eric Olson
(Li et al., 1995). Antibodies
against β-catenin (mouse, 1:1000; Sigma), and BrdU (mouse, 1:8; Roche)
were used. Appropriate secondary antibodies conjugated to biotin (1:250;
Vector Laboratories, Jackson ImmunoResearch) were used. For β-catenin
immunostaining, antigen retrieval was performed on paraffin sections by
boiling for 10 minutes in citrate buffer, then applying reagents from the
M.O.M. kit, and incubating overnight with the primary antibody (Vector
Laboratories). M.O.M. kit reagents were used as described by the manufacturer.
Brightfield images were captured using the Olympus BX60 microscope and Olympus
DP70 digital camera using DC Controller software. Whole-mount embryo images
were captured using a Leica MZ16F microscope, and a SPOT camera system and
software. Images were processed using Adobe Photoshop and Macromedia
Freehand.
Cell proliferation and survival studies
Embryos were collected and processed for proliferation and survival studies
as previously described (Atit et al.,
2006). To assess cell proliferation in embryos, BrdU incorporation
was detected by immunohistochemistry and quantified as previously described
(Atit et al., 2006). In
addition, antigen retrieval was performed by boiling for 10 minutes in citrate
buffer prior to the application of primary antibody. Statistical significance
(P>0.05) was determined by conducting a Student's t-test.
Analysis was restricted to En1 lineage-marked cells in the flank and
ventral subectodermal mesenchyme. Cell survival was assayed by brightfield
TUNEL staining on cryosections, as previously described
(Gavrieli et al., 1992),
before counterstaining with 2% methyl green for 2 minutes at room
temperature.
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RESULTS |
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SUMMARY
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MATERIALS AND METHODS
RESULTS
DISCUSSION
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). lacZ expression was present at embryonic
day 8.5 (E8.5) in the somatopleure of the LPM, and in the subectodermal
mesenchyme of the flank at E9.5 and E10.5
(Fig. 1A-C). By E11.5,
TCF/Lef-lacZ transgene expression was observed in the
subectodermal mesenchyme of the ventral midline
(Fig. 1D). By E14.5,
lacZ was expressed in a significant number of dermal cells, evenly
around and between hair follicles (Fig.
1E, inset). Wnt signaling reporter expression in embryonic skin
suggests a role in dermal differentiation and interfollicular dermal
development. In our analysis, we observed a similar expression pattern of the
TCF/Lef-lacZ transgene expression along the anteroposterior axis
until the level of the hind limb (data not shown). Prior to the onset of
expression of the earliest dermal progenitor marker Dermo1 at E11.5
(Fig. 6J), cells process Wnt
signaling in the dermal progenitors between E8.5 and E11.5
(Fig. 1A-D). These results
suggest that Wnt signaling may have roles in early and late ventral dermal
cell development.
Mouse ventral dermal cells originate from the lateral plate mesoderm
We used Cre/loxP tools to conduct lineage analysis of ventral
dermal cells. At the forelimb level, the HoxB6Cre transgene drives
the expression of Cre recombinase early in the LPM, starting at E8.0
and later (Lowe et al., 2000).
HoxB6Cre; R26R lineage-marked cells contributed extensively to the
ventral dermis by E16.5 (Fig.
2A). When we temporally restricted the recombination of
R26R, by using an inducible HoxB6Cre-ERT1 driver,
to the LPM tissue between E7.75-E8.75, we found β-gal+ cells
dispersed in the flank and ventral mesenchyme by E11.5, and then in the
ventral dermis at E17.5 (Fig.
2B-D). Lineage-marked cells were also present in the sternum and
endothelial cells in blood vessels, within muscle, and adjacent to the
sternum. (Fig. 2C,E).
Endothelial cells were identified by morphology and immunostaining with
anti-PECAM antibody (data not shown). In the absence of Tamoxifen, we did not
observe β-gal expression in these lineages (data not shown). Thus,
similar to the chick embryo, the ventral dermis in the mouse embryo originates
from the LPM.
The survival of early dermal progenitors requires β-catenin
To determine the function of Wnt signaling in mouse ventral dermal
development, we used the HoxB6Cre driver to genetically alter Wnt
signaling activity levels in the LPM, and analyzed mutants with a conditional
loss of β-catenin function in the flank and ventral subectodermal
mesenchyme. By E9.5, HoxB6Cre-mediated recombination of R26R
is nearly 100% in all the flank mesenchyme cells
(Lowe et al., 2000). We used a
loss-of-function floxed allele of β-catenin
(β-catlof) to eliminate Wnt signal transduction in
the HoxB6Cre lineage cells of the LPM
(Brault et al., 2001).
HoxB6Cre; R26R; β-catlof mutant embryos
lacked a ventral body wall and died between E12.5 and E13.5 (data not shown).
We examined the role of β-catenin in the cell survival of the early
dermal progenitors in the flank mesenchyme. At E9.5, there was no TUNEL
staining of the LPM in the control or in the HoxB6Cre; R26R;
β-catlof mutant (data not shown). By E10.5, we found
fewer HoxB6Cre, R26R lineage-labeled cells and a significant increase
in the TUNEL staining of cells in the flank mesenchyme of the
β-catlof mutant
(Fig. 3C,D). By comparison, we
did not find any TUNEL staining in the flank mesenchyme of the control
HoxB6Cre, R26R;β-catlof/+ lineage-labeled
cells at E10.5 (Fig. 3A,B).
These data demonstrate that β-catenin is required for the cell survival
of early dermal progenitors and perhaps, but not necessarily, the progenitors
of other tissues derived from the LPM.
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|
). En1Cre-mediated recombination of the R26R
was seen in essentially all of the subectodermal cells of the flank mesenchyme
starting at E10.5 (Fig. 4A,B),
and in the ventral mesenchyme at the midline by E11.5
(Fig. 4C,D).
En1Cre-mediated recombination of R26R at E10.5 coincides
with the spatiotemporal expression of TCF/Lef-lacZ
(Fig. 4B,
Fig. 1C) and precedes the onset
of Dermo1 expression at E11.5
(Fig. 6J).
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). To
lineage-mark En1-expressing cells in the ventral trunk between E10.75
and E11.75, we administered Tamoxifen to pregnant females carrying E10.5
En1Cre-ERT1; R26R embryos
(Sgaier et al., 2005). At
E16.5, β-galactosidase-labeled cells were found throughout the ventral
dermis (open arrows, Fig. 4F).
Our inducible lineage-marking experiments demonstrated that
β-galactosidase-labeled cells in the ventral trunk epidermis of
En1Cre; R26R embryos must arise as a result of En1
expression in the ventral trunk ectoderm starting at E13.5
(Fig. 4E,F; data not shown).
Therefore, the early development of mutant dermal progenitors in conditional
En1Cre; β-catenin mutant embryos occurred next to normal
overlying ventral ectoderm cells up until E13.5. In addition, between E9.5 and
E12.5, we did not see En1lacZ expression in the ventral trunk
ectoderm at the forelimb level (data not shown). Taken together, these results
suggest that En1Cre cells in the flank and ventral subectodermal
mesenchyme at E10.5 include ventral dermal progenitors and contribute
extensively to the ventral dermis.
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;
Harada et al., 1999;
Kimmel et al., 2000). To
determine the efficiency of En1Cre-mediated recombination of two
floxed alleles of β-catenin (Brault et
al., 2001; Harada et al.,
1999), we examined TCF/Lef-lacZ expression at E11.5 in
mutant embryos. In E11.5 En1Cre; β-catlof
embryos, TCF/Lef-lacZ was completely lost in cells of the
En1 lineage lacking β-catenin
(Fig. 1F, inset).
TCF/Lef-lacZ expression was present in normal forelimb mesoderm cells
that had not expressed En1Cre
(Fig. 1F, open arrows).
Similarly, when the En1Cre line was used to stabilize β-catenin
activity in the subectodermal mesenchyme, TCF/Lef-lacZ and nuclear
β-catenin were ectopically expressed in cells of the En1 lineage
away from the ectoderm (Fig.
1G, inset; Fig. 1D;
Fig. 4D; data not shown)
(Harada et al., 1999). By
E11.5, En1Cre can be used to efficiently eliminate or stabilize Wnt
signaling/β-catenin activity in ventral dermal precursors prior to dermal
specification (Fig. 6).
β-catenin is required for ventral dermal development
To determine the requirement of Wnt/β-catenin signaling later in
ventral dermal development, we used En1Cre to conditionally delete
β-catenin activity in ventral dermal precursors. We bred En1Cre,
R26R with the floxed β-catlof mice to
conditionally eliminate Wnt signal transduction and genetically tag the mutant
cells. En1Cre; R26R; β-catlof mutants die at
birth. At E16.5, En1Cre; R26R; β-catlof
mutants are smaller in size than control embryos, and have more transparent
ventral skin through which the liver can be clearly viewed (data not shown).
The development of epidermally-derived hair follicles is dependent upon normal
interaction with the dermis. In the absence of normal epidermal and dermal
interactions, hair follicles fail to form
(Atit et al., 2006;
Millar, 2002). To obtain an
overview of the affected area, we probed control and mutant embryos at E14.5
with antisense mRNA for patched 1 (Ptch1), a marker for hair follicle
placodes (Oro et al., 1997).
At E14.5, Ptch1 was expressed in the hair follicle placodes of the
control embryo (Fig. 5A), but
was completely absent in the ventral flank and midline of En1Cre;
β-catlof mutant embryos
(Fig. 5B). In transverse
sections of a E16.5 En1Cre; R26R control fetus, the epidermis
overlaid the condensed dermis, ventral muscle and sternum
(Fig. 5C,E,G). By striking
contrast, the En1Cre; β-catlof fetuses
lacked ventral dermis and muscle, and the epidermis was juxtaposed next to the
sternum (Fig. 5D,F,H). En1
lineage-marked cells contributed extensively to the sternum and were absent in
the adjacent rib cartilage (Fig.
5E,I). In the En1Cre; R26R;
β-catlof fetus, we found that the sternum, with
lineage-marked cells, extended across the entire ventrum
(Fig. 5F,H,J). The rib also
lacked lineage-marked cells in the mutant embryos
(Fig. 5F,J). We could not study
dermal development in the complementary En1Cre;
β-catgof mutants owing to embryonic lethality between
E12.5 and E13.5. The late stage En1Cre;
β-catlof phenotype illustrates that
β-catenin/Wnt signaling activity is needed for ventral dermal
development.
|
; Li et al.,
1995). At E10.5, Dermo1 was not expressed in the control
flank subectodermal mesenchyme (Fig.
6A,D). Dermo1 was normally detectable starting at E11.5
in the En1 lineage-marked flank and ventral subectodermal mesenchyme
(Fig. 6G,J). In the conditional
absence of Wnt signaling/β-catenin activity in the En1 lineage,
Dermo1 was not expressed at E10.5 or E11.5 in the flank and ventral
subectodermal mesenchyme (Fig.
6B,E,H,K). By contrast, conditionally stabilizing β-catenin
activity in the En1 lineage led to the induction of Dermo1
mRNA expression earlier at E10.5 (Fig.
6C,F) and to ectopic expression in most of the En1Cre;
R26R; β-catgof mutant cells at E11.5
(Fig. 6I,L). Dermo1
expression in the two different β-catenin activity mutants clearly
demonstrates that β-catenin activity is required for the onset of ventral
dermal progenitor marker expression and dermal specification.
β-catenin regulates cell proliferation of ventral dermal progenitors
Next, we examined the role of β-catenin in the cell proliferation and
cell survival of ventral dermal progenitor cells at these later stages.
Because the specification defect phenotype is evident by E11.5 in both the
conditional mutants, we analyzed embryos for alterations in cell proliferation
and cell survival at E10.5 and E11.5 (Fig.
7, Table 1). We
examined cell proliferation by BrdU incorporation. There was no statistically
significant difference (P<0.05) in the cell proliferation index
between the control and the En1Cre; R26R;
β-catlof or β-catgof at
E10.5 (Table 1). At E11.5, we
found a statistically significant difference in cell proliferation between
control and En1Cre; β-catlof embryos only,
and not with β-catgof mutants
(Fig. 7A-C,
Table 1). We assayed cell
survival by TUNEL and could not find any significant changes in cell survival
between control and En1Cre; β-catlof or
β-catgof at E10.5 and E11.5
(Fig. 7D-F; data not
shown).
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DISCUSSION |
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SUMMARY
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MATERIALS AND METHODS
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DISCUSSION
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).
Consistent with the fate maps from the chick embryo, we find lineage-labeled
cells in known derivatives of the LPM in ventral trunk tissues, such as the
body wall mesenchyme, at E11.5, and later in the dermis, sternum, and
endothelial cells by E16.5. As expected, we do not see lineage-labeled cells
in the ribs derived from the somites or in the epidermis, which differentiates
from the surface ectoderm. We confirmed our ventral dermis fate map by using
the En1Cre and En1Cre-ERT1 lines, which drive
expression later at E10.0 in the flank and ventral mesenchyme. We find
β-gal+ cells extensively in the ventral dermis, the dermal
papillae of the hair follicles, and the sternum. Our results from multiple
genetic lines and strategies demonstrate clearly that LPM cells contribute to
the body wall mesenchyme by E11.5, and then later to ventral dermis in the
mouse embryo. Our fate mapping results have aided our analysis of the
β-catenin conditional mutant phenotypes.
Multiple roles for Wnt signaling/β-catenin in ventral dermal cell development
Wnt signaling reporter activity is evident in the somatopleure of the LPM
starting at E8.5, and then in the subectodermal mesenchyme of the flank and
ventrum. The Wnt signaling reporter activity is consistent with the known
expression of multiple Wnt ligands in the surface ectoderm of the mouse embryo
(Cauthen et al., 2001;
Parr et al., 1993), and with
signaling to the mesenchyme cells directly below. These subectodermal
mesenchyme cells process the Wnt signal and differentiate to ventral dermis.
The additional lineage-marked cells located away from the surface ectoderm
must differentiate into other cell types. Our complementary results from
mutants with conditional loss- and gain-of-β-catenin function, clearly
demonstrate that β-catenin has a role early in cell survival and later in
the cell specification of ventral dermal progenitors. In this study, by
eliminating β-catenin early in the LPM, we found a role for
β-catenin in early cell survival before E10.5. When we eliminated
β-catenin after E10.0, the subectodermal cells survived but failed to be
specified to the ventral dermal cell fate by E11.5. In our previous studies on
dorsal dermis, we eliminated β-catenin early in the multipotential
progenitors of the somite and demonstrated that β-catenin has an
instructive role in dermal cell fate from the somite, but we did not see a
role in the cell survival of dermal progenitors
(Atit et al., 2006). In this
study, we found that β-catenin has a new role in ventral dermal
progenitor cell survival while maintaining a functionally conserved role in
dorsal and ventral dermal cell fate selection.
Our fate mapping results demonstrate that we have marked cells that originate in the LPM and that contribute to sternal cartilage, ventral dermal and endothelial cell lineages. The En1Cre; R26R; β-catlof mutant shows an absence of ventral dermal specification and a significant expansion of the sternum. The sternum, containing lineage-labeled cells, traverses the width of the embryo. It is not clear whether the mutant ventral dermal progenitors are respecified to sternum fate. The small decrease in cell proliferation could account for a decrease in dermal progenitor population. Taken together with the absence of cell death, some of the dermal progenitors may also be respecified to the sternum cell fate.
It still remains to be determined how Wnt signal transduction instructs
subectodermal mesenchyme in the flank and trunk to progress towards the
ventral dermal cell fate. Wnt signaling/β-catenin activity is crucial for
Dermo1 gene expression in dorsal and ventral dermal progenitors, and
Dermo1 may be the direct target gene to promote dermal cell fate
(Atit et al., 2006)
(Fig. 6). Identifying the
additional downstream target genes and defining the genetic program for dermal
cell development are the next steps in understanding dermal cell
differentiation.
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ACKNOWLEDGMENTS |
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REFERENCES |
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TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
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