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First published online 26 March 2008
doi: 10.1242/dev.019331
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1 Max-Planck-Institute for Heart and Lung Research, Parkstr. 1, 61231 Bad
Nauheim, Germany.
2 Human Genetics Division, University of Southampton, Southampton SO16 6YD,
UK.
Author for correspondence (e-mail:
thomas.braun{at}mpi-bn.mpg.de)
Accepted 25 February 2008
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SUMMARY |
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 TOP SUMMARY INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key words: Skeletal muscle, Cell ablation, Myf5, Myogenic cell lineages
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INTRODUCTION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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).
Myogenic progenitor cells become restricted to the epithelium of the
dermomyotome when somites mature
(Buckingham, 2006). After
delamination of cells from the dermomyotomal layer, myogenesis starts by
stable expression of the myogenic regulatory factor (MRF) Myf5 followed by
expression of myogenin, Myf6 (also called MRF4) and finally Myod1
(Neuhaus and Braun, 2002).
Specification, proliferation and terminal differentiation of skeletal muscle
cells is controlled by the combinatorial activities of MRFs, which, together
with the paired domain transcription factors Pax3 and Pax7, are essential for
skeletal myogenesis (Buckingham,
2006; Neuhaus and Braun,
2002).
We have shown previously that combined inactivation of Myf5 and MyoD mice
causes a complete lack of skeletal muscle formation
(Rudnicki et al., 1993), while
inactivation of Myf5 and Myod1 alone results in the absence of the first wave
of muscle cells (Myf5); (Braun et al.,
1992) or in a moderate muscle phenotype (Myod1)
(Megeney et al., 1996). More
recently, it has been demonstrated that the original inactivation of the Myf5
gene also compromises expression of Myf6 at early developmental stages and
that Myf6 partially rescues embryonic myogenesis in a new strain of Myf5/Myod1
double-knockout mice (Kassar-Duchossoy et
al., 2004), although fetal myogenesis was severely compromised and
other new strains of Myf5/Myod1 double-mutant mice were also essentially
devoid of skeletal muscle at birth (Kaul
et al., 2000).
The absence of lasting muscle abnormalities in mice lacking either
Myf5/Myf6 or Myod1, and the complete lack of skeletal muscle cells in compound
Myf5/Myf6/Myod1 mutant mice suggested that MRFs play functionally overlapping
roles during muscle cell development. In order to distinguish whether
Myf5/Myf6 and Myod1 substitute for each other within the same cell lineage or
whether, alternatively, each factor determines a distinct muscle cell
population we previously ablated Myf5-expressing cells in ES-cell derived
skeletal muscle cells using a HSV thymidine suicide gene inserted into the
Myf5 locus (Braun and Arnold,
1996). Although we were able to demonstrate that complete ablation
of Myf5-expressing muscle precursor cells from differentiating ES cells does
not abrogate Myod1-dependent muscle cell differentiation in vitro
(Braun and Arnold, 1996), the
nature of compensation between Myf5/Myf6 and Myod1
genes has been questioned. In particular, it has been claimed that Myf5 acts
upstream of Myod1, as Myod1 expression in somites was delayed until after
E10.5 in Myf5nlacZ/nlacZ embryos
(Tajbakhsh et al., 1997). This
statement was later modified, as Myod1 expression was detected before E10.5 in
Myf5 mutants, in which Myf6 expression was not compromised
(Kassar-Duchossoy et al.,
2004; Kaul et al.,
2000). The existence of parallel cell lineages determined by
individual bHLH genes has also been demonstrated in the nervous system where
Ngn2 and Ngn1 determine two genetically and lineally distinct populations of
sensory neuron precursors, which can be both independently regulated in
distinct sensory lineages, as well as crossregulated within a given lineage.
The neurogenesis defect in Ngn2 mutant embryos is transient (as in Myf5 mutant
mice) and later compensated for by Ngn1-dependent precursors, suggesting that
feedback or competitive interactions between these precursors may control the
proportion of different neuronal subtypes they normally produce
(Ma et al., 1999).
To demonstrate that Myf5 is expressed only in a distinct population of muscle precursor cells and hence determines only a subset of muscle cells, we have employed an in vivo conditional cell ablation approach based on activation of the diphteria toxin A-chain (DTA) by Cre-recombinase. Activation of DTA in Myf5-Cre-expressing cells erased all Myf5-expressing cells until E15.5, which included the majority of early muscle cells in somites. Ablation of early muscle cells was fully rescued by another, Myf5-independent, cell population, demonstrating initiation of the muscle program in autonomous cell populations. Interestingly, however, later aspects of the myogenic program are shared among all populations of muscle cells as the ablation of myogenin-expressing cells erased virtually all differentiated muscle cells at E18.5. We also detected malformations of the axial skeleton in Myf5-Cre/DTA mice, which might be due to transient activation of the Myf5 gene in the unsegemented paraxial mesoderm.
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MATERIALS AND METHODS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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), of
the Rosa26lacZ Cre-reporter strain
(Soriano, 1999), of
myogenin-Cre mice (Li et al.,
2005), of R26:lacZ/DT-A (DTA) effector mice
(Brockschnieder et al., 2004)
and of Z/AP reporter mice (Lobe et al.,
1999) have all been described before. Mice were crossed to and
maintained on a C57/BL6 background and genotyped by Southern blot analysis or
PCR.
Immunofluorescence, in situ hybridization, lacZ staining and skeletal analysis
For immunofluorescence and histological staining, cryosections were
prepared and processed applying standard procedures
(Schulze et al., 2005;
Ustanina et al., 2007). The
following antibodies were used: MF20 (DSHB), anti-myogenin (DSHB), anti-Myf5
(Santa Cruz), anti-Myod1 (clone 5.8A, Dako GbmH) and anti-Pax7 (DSHB).
Secondary antibodies were coupled with Alexa 594 (red) and Alexa 488 (green),
and used according to the manufacturer's instructions (Molecular Probes).
Whole-mount in situ hybridization with digoxigenin-labeled antisense cRNA
probes and sectioning of stained embryos were performed as described
previously (Schafer and Braun,
1999). lacZ staining was performed as described
previously (Oustanina et al.,
2004). Alkaline phosphatase staining was done on cryosections
using the Vector Red Alkaline Phosphatase Substrate Kit I (Cat. No. SK-5100),
according to the instructions supplied by the manufacturer (Vector Labs). For
bone and cartilage staining, fetuses were processed as described
(Kaul et al., 2000).
RNA isolation and RT PCR
Isolation of RNA was carried out using established procedures that have
been described previously (Schulze et al.,
2005; Ustanina et al.,
2007). RT-PCR analysis was essentially done as described
(Schulze et al., 2005).
Detailed protocols and primer sequences are available from the authors on
request. In all cases, housekeeping genes such as ribosomal acidic protein
(RAP) or glycerinaldehyde-3-phosphate dehydrogenase (GAPDH), were used as
internal controls. Identities of PCR products were corroborated by DNA
sequence analysis.
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RESULTS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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).
Subsequently, several waves of muscle cells form and give rise to various
muscles of the body. To investigate whether all muscle cells were derived from
Myf5-expressing cells (referred to as Myf5-derived cells in this paper) or
whether the Myf5 lineage contributes to the cellular heterogenity of muscular
cells, as suggested by previous experiments using ES-cell derived skeletal
myocytes (Braun and Arnold,
1996), we crossed Myf5-Cre mice, which carry a Cre-recombinase
inserted into the Myf5 locus (Tallquist et
al., 2000), with a Rosa26lacZ Cre-reporter strain
(Soriano, 1999). The same
Myf5-Cre strain has been employed in a number of studies to trace
Myf5-expressing cells in satellite cells of adult mice
(Kuang et al., 2007) or to
delete genes in skeletal muscle (Wang et
al., 2005). A strong expression of the lacZ reporter gene
was observed at E10.5 (Fig.
1C-F). Interestingly, the expression was not only confined to the
myotome but was also found in other parts of the embryo such as the
dermomyotome and the sclerotome, which are derived from the paraxial mesoderm.
Most likely, this expression was due to a transient activity of the Myf5
promoter in the paraxial mesoderm, which was not detectable by direct
visualization of Myf5 promoter activity
(Tajbakhsh et al., 1997). To
further explore this possibility, we performed a RT-PCR analysis of the
expression of MRFs in the paraxial mesoderm and the head of E8.5 embryos.
After 35 amplification cycles, we detected an expression of Myf5 in the
unsegmented paraxial mesoderm but not in the head region (see Fig. S1 in the
supplementary material). A very faint signal was also found for Myf6 but not
for Myod1 and myogenin.
We also observed numerous lacZ-positive cells in the neural tube
and the brain (data not shown), which corroborates previous reports about the
activity of the Myf5 gene during embryogenesis
(Tajbakhsh and Buckingham,
1995; Tajbakhsh et al.,
1994). Five days later, at E15.5, most lacZ-positive
cells were located within skeletal muscle masses of the trunk, head and limbs
(Fig. 1G,J and data not shown),
although some lacZ-positive cells were also found in cartilage cells
of the axial skeleton (ribs and vertebrae) and in the dermis, which reflects
their origin from the paraxial mesoderm
(Fig. 1). Only relatively few
lacZ-positive cells remained in tissues derived from the neural tube
(Fig. 1K), suggesting an active
removal of Myf5-derived cells from certain tissues. Surprisingly, the
distribution of Myf5-derived cells among different muscles varied. In some
muscles, the majority of muscle cells were labeled, while in other muscles (as
for example the diaphragm) the contribution was limited (arrows in
Fig. 1G and data not shown). We
also noted significant differences in the contribution of Myf5-derived cells
to separate muscles among individual mice, suggesting that the distribution of
Myf5-derived cells was controlled by a stochastic mechanism. We did not find
evidence for an increased presence of Myf5-lineage derived cells in
autochthone muscles of the back or in limb muscles, which argues against a
specific role of Myf5-expressing cells in the formation of epaxial and
hypaxial muscles.
|
).
Breeding of myogenin-Cre mice (Li et al.,
2005) with a Rosa26lacZ Cre-reporter strain
(Soriano, 1999) led to
lacZ expression in the myotome of the most mature somites at E9.5
(Fig. 1A,B). At E15.5 virtual
all muscle cells were positive for lacZ (see Fig. S2 in the
supplementary material), confirming the indispensable role of myogenin for
embryonic muscle differentiation.
The myogenic lineage is established from multiple independent muscle progenitor populations
Previously, we have demonstrated that ablation of Myf5-expressing muscle
precursors cells did not prevent Myod1-dependent muscle cell differentiation.
The system employed was based on ES cells engineered to carry the HSV TK
suicide gene in one allele and the lacZ reporter gene in the other
allele of the Myf5 gene (Braun and Arnold,
1996). Although ES cell-derived skeletal myoblasts offer some
experimental advantages they lack the complexity of normal embryonic
development. In addition, more subtle changes in the spatial and temporal
distribution of myogenic cell populations might be obscured in the in vitro
model (Braun and Arnold, 1994).
We therefore turned to an in vivo cell ablation system that uses
Cre-recombinase-mediated activation of the diphteria toxin A-chain (DTA). To
examine the efficiency of DTA-mediated elimination of Myf5-derived cells, we
crossed Myf5-Cre mice to Z/AP reporter mice, which activate the alkaline
reporter gene instead of the lacZ reporter gene upon
Cre-recombinase-mediated recombination
(Lobe et al., 1999). The use
of Z/AP mice was necessary as our R26//lacZ/DT-A (DTA) effector mice express
lacZ ubiquitously (Brockschnieder
et al., 2004). At E15.5, skeletal muscles were labeled by AP
activity (Fig. 2A,C,E)
comparable with Myf5-Cre//Rosa26lacZ mice. We next crossed Myf5-Cre//Z/AP mice
to R26//lacZ/DT-A (DTA) mice and found that Myf5-Cre//DTA//Z/AP embryos were
essentially devoid of any Myf5-derived cell at E15.5, as indicated by the
absence of AP-positive cells (Fig.
2B,D,F).
Similar to Myf5-Cre//Rosa26lacZ mice, we observed variations in the distribution of Myf5-derived cells among different muscles, suggesting that this phenomenon was not due to a variable expression from the Rosa26lacZ or from the unrelated Z/AP locus. Interestingly, mice lacking Myf5-derived cells did not show a significant loss of muscle masses, as judged from differential interference contrast microscopy (Fig. 2B,D,F). Immunofluorescence analysis of muscles of Myf5-Cre//DTA mice at E14.5 and E18.5 using an antibody against MyHC (MF-20) confirmed the normal formation of skeletal muscles in the absence of Myf5-derived myogenic cells (Fig. 3A,D,G,J). By contrast, myogenin-Cre//DTA mice failed to form differentiated muscle at E18.5 (Fig. 3E,H,K). The formation of essentially normal skeletal muscles at E18.5 in Myf5-Cre//DTA and the loss of muscles masses in myogenin-Cre//DTA at this stage were also confirmed by inspection of Hematoylin and Eosin-stained tissues sections (see Fig. S3 in the supplementary material). Efficient killing of muscle cells in myogenin-Cre//DTA mice was not apparent before E14.5, indicating a considerable delay between the onset of promoter activity that drove Cre-recombinase expression, recombination of the DTA locus and DTA-mediated cell death (Fig. 3B and data not shown).
Clearly, embryos were able to compensate for the ablation of Myf5-derived cells to form normal skeletal muscles but not for the absence of cells that had expressed myogenin. This finding was also supported by a preliminary DNA microarray-based analysis of Myf5-Cre//DTA E14.5 embryos using the GeneChip Mouse Genome 430 2.0 Array (Affymetrix). Only very few structural muscle genes were significantly changed in Myf5-Cre//DTA mice compared with wild-type controls, indicating a relatively normal formation of skeletal musculature (see Table S1 in the supplementary material). The complete dataset of the microarray experiment has been deposited in the ArrayExpress repository (Accession Number E-MEXP-1486). Apparently, muscle cells that developed from non-Myf5-derived cells generated a similar expression profile to Myf5-derived cells, which suggested a similar developmental potential of Myf5-derived and non-Myf5-derived muscle progenitor cells. The DNA microarray analysis also revealed a decrease of Myf5 expression and a reduction of the expression of Myf6 of a log ratio of 1.8. Owing to the low expression level of Myf5 at E14.5, the decline of Myf5 expression appeared comparatively modest (see Table S1 in the supplementary material).
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Immunofluorescence analysis of Myf5-Cre//DTA, myogenin-Cre//DTA and wild-type mice at E10.5 revealed a complete loss of cells that expressed Myf5 protein (Fig. 5A,D,G). The ablation of Myf5-expressing cells was already starting 1 day earlier at E9.5, as indicated by the significant reduction of the number of cells that stained positive for Myf5 protein, although some remaining cells were clearly visible at this stage (see Fig. S4 in the supplementary material). At E10.5, we also observed a massive reduction of the number of Myod1 and myogenin-expressing cells, which occurred concomitant with the loss of Myf5-positive cells (Fig. 5A,D,G). The remaining Myod1 and myogenin-positive cells were scattered within the somites (Fig. 5A,G), which had lost their regular architecture (Fig. 5A,D,G). Pax7-positive cells were found only at the dorsolateral and ventromedial edges of the dermomyotome, while the central area was devoid of Pax7 expression (Fig. 5D). The induction of cell death by Cre recombinase-mediated activation of DTA was also accessed directly using the TUNEL assay. We detected a large number of TUNEL-positive apoptotic cells in somites of Myf5-Cre//DTA mice at E9.5 and E10.5, but only a comparatively small number of apoptotic cells was present in somites of wild-type mice (see Fig. S5 in the supplementary material). No reduction of Myf5, myogenin, Myod1 or Pax7 was observed in myogenin-Cre//DTA embryos at E10.5, which corresponds to the later onset of expression of the myogenin-Cre and the activity of the myogenin-promoter in differentiating muscle cells. Similar to the loss of cells that stained positive for Myf5 protein, using RNA in situ hybridization we observed a loss of cells that expressed Myf5 mRNA at E10.5 in cranial somites (see Fig. S6B in the supplementary material). In the caudal part of Myf5-Cre//DTA embryos, residual amounts of Myf5 mRNA-positive cells were still detectable (see Fig. S6H in the supplementary material) reflecting the ongoing process of cell ablation, which was completed only at E15.5 (Fig. 2). Similarly, no mRNAs for Myod1 and myogenin were detected in cranial somites at E10.5 (see Fig. 6D,F in the supplementary material), although some signals were present in caudal somites (see Fig. S6J,L in the supplementary material). The localization of signals in caudal somites was aberrant, again reflecting the continuing process of cell death and the resulting disorganization of the somites. In our view, the persistent presence of some dislocated Myf5 transcripts within somites of Myf5-Cre//DTA embryos (see Fig. S6H in the supplementary material) in the absence of Myf5 protein reflects the delay between the onset of Myf5-Cre-, Cre-recombinase-mediated DTA activation and cell death.
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Myf5-Cre//DTA mice die perinatally due to severe malformations of the axial skeleton
Both Myf5-Cre//DTA and myogenin-Cre//DTA were born at normal Mendelian
ratios but died shortly after birth. Although we expected this outcome for
myogenin-Cre//DTA mice, which lacked all skeletal muscles at E18.5, the
perinatal death of Myf5-Cre//DTA, which did not show any major alterations of
the skeletal musculature at E18.5, was a surprise. As we observed the presence
of Myf5-derived lacZ-positive cells in the cartilage of the axial
skeleton at E15.5 (Fig. 1G,H),
we decided to analyze the skeleton of newborn Myf5-Cre//DTA mice by Alcian
Blue/Alizarin Red staining. We detected major deformities of the axial
skeleton, including fusion of ribs and vertebrae, lack of distal and proximal
parts of the ribs and other defects (Fig.
7). In general, the observed malformation were variable and
severe, thus differing from the stable phenotype, which we have observed
previously in Myf5 mutant mice and which always affected only the distal parts
of the ribs (Braun et al.,
1992).
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DISCUSSION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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) and a direct knock-in of the lacZ reporter into the
Myf5 locus (Tajbakhsh et al.,
1996a) showed a much more restricted expression pattern of Myf5,
which reflects the difference between permanent cell tracing and temporarily
restricted gene activity. Although the β-galactosidase protein is rather
stable in certain cells, transient activity of a promoter might escape
detection or might not suffice to generate sufficient amounts of a reporter
protein. The relatively broad presence of Myf5-derived cells in tissues
originating from the paraxial mesoderm and the neuroectoderm in
Myf5-Cre/Rosa26lacZ embryos might be explained in two ways: (1) aberrant
activity of the Myf5-Cre inserted into the Myf5 locus, which causes
lacZ-activation in tissues derived from the paraxial mesoderm and the
neural tube; or (2) transient activity of the Myf5 promoter in the paraxial
mesoderm, which was not detectable by direct visualization of Myf5 promoter
activity as described by Tajbakhsh et al.
(Tajbakhsh et al., 1996a). The
fact that Myf5-derived cells were confined to tissues of the paraxial mesoderm
and the neural tube at E9.5 and E10.5, and not in uncharacteristic locations
within the embryo makes an aberrant activity of Myf5-Cre at E9.5 and E10.5
unlikely. Usually, it takes 1-2 days until the recombination initiated by
Cre-recombinase is completed and cell labeling occurs, which suggests that the
presence of lacZ-positive cells at E9.5 and E10.5 was due to an
activity of Myf5-Cre at earlier time points. A transient activity of the Myf5
promoter in the paraxial mesoderm around E8 would explain the observed
presence of Myf5-derived cells in progeny of the paraxial mesoderm. In fact,
we were able to detect a low-level expression of Myf5 in unsegmented paraxial
mesoderm by RT-PCR. Similar observations were also made in our laboratory
several years ago, which were neglected at that time as no further evidence
for an activity of the Myf5/Myf6 locus in the unsegemented paraxial mesoderm
existed (data not shown). Moreover, further evidence for an activity of the
Myf5 promoter in unsegmented mesoderm comes from other species. In the
zebrafish, Chen et al. have described a significant expression of Myf5 in the
unsegemented paraxial mesoderm (Chen et
al., 2001). It is also intriguing to see that cells that carry a
homozygous mutation of the Myf5 gene are able to contribute to other
somitic derivatives, according to their local environment
(Tajbakhsh et al., 1996b),
including the axial skeleton and the dermis, exactly the tissues that also
harbor Myf5-derived cells. In our view, this observation further supports the
hypothesis that a transient activity of the Myf5 promoter occurs in
multipotent cells of the paraxial mesoderm, which is later stabilized by
specific positional cues eventually leading to the characteristic Myf5
expression profile (Buckingham,
2001). Taken together, our results indicate that the activity of
the Cre-recombinase inserted into the Myf5 locus faithfully recapitulates (a
transient) expression of Myf5 in the paraxial mesoderm, although we cannot
rule out completely that the insertion of the cre-recombinase gene into the
Myf5 locus affected its regulation. The latter caveat might principally be
raised for all reporter genes inserted by targeted recombination.
|
|
). Although
the skeleton phenotypes of Myf5m1 and Myf5-Cre//DTA mice are caused
by different effects and vary significantly between both strains, they both
reveal the vulnerability of the formation of the axial skeleton. Unlike the
skeletal muscle lineage (and probably dermal cells), which are able to
compensate even major losses of cells, the axial skeleton seems to lack this
ability. It is tempting to speculate that the compensatory potential of the
skeletal muscle lineage is based on the high proliferative and migratory
capacities of fetal myoblasts, a property that is also maintained throughout
adult life and accounts for the exceptional regenerative capacity of skeletal
muscle.
Our study clearly demonstrates that only a subset of myogenic cells
expresses Myf5 and that this cell population is one among others, which form
the skeletal muscle lineage. Interestingly, the Myf5-derived cell population
seems not to coincide with any known myogenic cell lineage as, for example,
epaxial or hypaxial cells, which have been proposed to depend differentially
on Myf5 and Myod1 (Kablar et al.,
1997), and on fast or slow muscle cells
(Biressi et al., 2007). This
raises the question about the functional importance of Myf5-derived cells. As
our previous in vitro studies using ES cell derived skeletal myoblasts
suggested the existence of Myf5-independent muscle cell lineages, it was
surprising to see that most of the early Myod1 expressing cells were killed
during early somitogenesis. These results might be explained by the activation
of the Myod1 gene in most Myf5-expressing cells, which also corresponds to the
co-expression of Myf5 and Myod1 in established muscle cells lines and at later
stages of fetal skeletal muscle development. A distinct cell population,
however, was obviously independent of Myf5 and expressed Myod1. These cells,
which need further characterization, allowed expansion of the myogenic cell
lineage and efficient rescue of myogenesis. It is also interesting to note
that the lack of the primary wave of muscle cells in Myf5 knockout mice were
also compensated efficiently during embryogenesis, resulting in essentially
normal musculature in adult Myf5 knockout mice
(Gayraud-Morel et al., 2007;
Ustanina et al., 2007). Based
on the preliminary DNA microarray analysis at E14.5 and the regular formation
of skeletal muscles at E18.5, the Myod1-dependent cell lineage did not show
major differences to the heterogeneous mix of cell populations that develop
normally, indicating a high degree of plasticity and adaptability.
|
). Using the same Myf5-Cre strain that was employed in this
study and a ROSA26-YFP Cre-reporter strain, it has been described that 10% of
sublaminar Pax7-positive satellite cells did never express Myf5
(Kuang et al., 2007). As
Pax7+/Myf5- satellite cells gave rise to
Pax7+/Myf5+ satellite cells through asymmetric cell
division, Kuang et al. argued that Pax7+/Myf5- are on
top of a hierarchy of muscle stem cells that give rise to new
(Pax7+/Myf5-) stem cells and to committed
(Pax7+/Myf5+) myogenic progenitors. Our finding that
Myf5 myogenic cells form only a subset of muscle cells, therefore contributing
to the heterogeneity of muscle cells during development, raises the question
whether Pax7+/Myf5- cells did indeed never see a muscle
regulatory factor of the Myf5/Myod1 family and thus belong to a more immature
muscle stem cell lineage. Alternatively, it might be envisaged that
Pax7+/Myf5- cells depend on other MRFs and thus do not
belong to the Myf5-derived muscle cell population. The widespread presence of
Myod1-derived satellite cells in adult muscles (David Goldhammer, University
of Connecticut, personal communication; N.G., T.B., A.S., D.R. and T.B.,
unpublished) does also argue in this direction. It will be interesting to
determine whether Pax7+/Myf5- cells are derived from
Myod1- or Myf6-expressing cells or developed from a Pax7/Pax3 cell population
(Relaix et al., 2005).
Supplementary material
Supplementary material for this article is available at
http://dev.biologists.org/cgi/content/full/135/9/1597/DC1
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ACKNOWLEDGMENTS |
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Footnotes |
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