1 Département de Biologie du Développement, CNRS URA 2578,
Institut Pasteur, 25 rue du Dr Roux, 75015 Paris, France
2 Section of Gene Function and Regulation, The Institute of Cancer Research,
Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, UK
Author for correspondence (e-mail:
margab{at}pasteur.fr)
Accepted 16 April 2003
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SUMMARY |
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Key words: Myf5, Mouse embryo, Myogenesis, Transcriptional regulation, BACs, Myotome, Limb, CNS
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INTRODUCTION |
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During embryogenesis, the spatiotemporal expression of Myf5 marks
skeletal muscle precursor cells and sites of myogenesis (see
Tajbakhsh and Buckingham,
2000). In newly formed somites, it is expressed before the other
myogenic factors, in the epaxial part of the dermomyotome, adjacent to the
neural tube. This is the first source of muscle precursor cells, which
involute and migrate from this epithelium to form the first differentiated
skeletal muscle, the myotome. The hypaxial extremity of the dermomyotome and
later somitic bud is also a source of muscle precursors, which express
Myf5 and form the hypaxial myotome, the origin of intercostal and
body wall muscles (Christ et al.,
1983
). This part of the dermomyotome, in somites at the
appropriate axial level, also gives rise to cells which migrate to other sites
of myogenesis, to the limb buds or, via the hypoglossal chord
(Mackenzie et al., 1998
;
Noden, 1983
), to the pharynx,
tongue and probably also diaphragm
(Tremblay et al., 1998
). Cells
that migrate to the limb do not express Myf5 until they reach their
destination (Tajbakhsh and Buckingham,
1994
). Myf5-positive cells are already present in the hypoglossal
cord where, in contrast to the limb progenitors, they do not migrate as
separate mesenchymal cells, but rather as a coherent cell mass
(Noden, 1983
). Myf5
is also expressed in the branchial arches in cells derived from anterior
paraxial mesoderm which will contribute to the formation of facial muscles. An
unexpected site of Myf5 expression is in neurones, in prosomeres p1
and p4 of the brain (Tajbakhsh and
Buckingham, 1995
) and in a ventral domain of the neural tube
(Tajbakhsh et al., 1994
). The
Myf5 protein does not accumulate in the central nervous system and there is no
detectable neuronal perturbation in the Myf5 mutant embryos
(Daubas et al., 2000
).
The molecular mechanisms that lead to Myf5 activation at these
multiple sites in the embryo are largely unknown. Signals from the axial
structures, neural tube and notochord, and from surface ectoderm are required
for the initiation of myogenesis in the somite in the mouse
(Summerbell and Rigby, 2000;
Tajbakhsh and Buckingham,
2000
), as in the avian embryo
(Christ and Ordahl, 1995
).
Sonic hedgehog from the notochord and floor plate of the neural tube, as well
as Wnt proteins produced by the dorsal neural tube and surface ectoderm, have
been implicated in Myf5 activation, which is particularly responsive
to ß-catenin-dependent Wnt1 signalling, as shown in mouse embryo explants
of presomitic mesoderm or immature somites
(Borycki et al., 1999
;
Tajbakhsh et al., 1998
).
Expression of Myf5 in explants from the region of the brain where the
gene is transcribed also responds in this way to Wnt1, leading to the
suggestion that this may reflect misfiring of a regulatory element that
normally directs Myf5 transcription in the somite, in response to the
Wnt1 signal (Daubas et al.,
2000
).
The multiple regulatory elements that direct the complete spatiotemporal
expression pattern of Myf5 in the embryo have been mapped within 145
kb of genomic DNA by YAC (Hadchouel et
al., 2000) and BAC (Carvajal et
al., 2001a
) transgenic analysis. Another gene, which encodes the
myogenic regulatory factor Mrf4, lies 7 kb 5' of the Myf5 gene
(Braun et al., 1990
;
Miner and Wold, 1990
). Within
this intergenic region, just 3' of the Mrf4 gene, an enhancer
element has been identified that directs early expression of Myf5 in
the epaxial dermomyotome (Summerbell et
al., 2000
; Teboul et al.,
2002
). Gustafsson et al. have reported that this element responds
to sonic hedgehog signalling, which is required for the expression of
Myf5 specifically in this epaxial domain
(Borycki et al., 1999
;
Gustafsson et al., 2002
). Also
in the intergenic region between Mrf4 and Myf5, further
regulatory regions have been described, including one that directs expression
to the branchial arches (Patapoutian et
al., 1993
; Summerbell et al.,
2000
) and another that leads to expression in the neural tube
(Summerbell et al., 2000
).
Within the Myf5 gene itself, an enhancer that directs expression to
the hypaxial domain of the somite has been identified
(Summerbell et al., 2000
). In
the genomic DNA lying upstream of the Mrf4-Myf5 genes, there
are a number of regulatory regions, including one responsible for maintenance
of Myf5 expression (-88 kb to -81 kb) in some muscles of the trunk
and head and others responsible for aspects of Myf5 expression in the
hypaxial somite, arches and hypoglossal cord
(Carvajal et al., 2001a
;
Carvajal et al., 2001b
;
Hadchouel et al., 2000
). In
particular, a sequence lying between -58 kb and -48 kb from the Myf5
gene (Hadchouel et al., 2000
)
directs expression of a transgene to sites of myogenesis in the somites,
hypoglossal cord and limb buds, as suggested by deletions in this region
(Carvajal et al., 2001a
;
Zweigerdt et al., 1997
), and
also to the brain. In this paper, we present the analysis of this region and
show that it is necessary for transcription of Myf5 at these sites in
the embryo. Different sites are targeted by distinct sequences and,
furthermore, within a single site, regulatory subdomains emerge that are
identified by dissection of the region or revealed after its deletion.
Unexpectedly, a distinct sequence targets transcription of Myf5 to
the central nervous system. At least three sequences are active at different
times and to varying extents in fore- versus hindlimbs. In the somite,
Myf5 expression is regulated by a minimum of six different sequences,
with more than one regulatory module required even within an ostensibly
uniform structure such as the myotome. The fine analysis of the region located
between -58 kb and -48 kb from Myf5, and the consequences of its
deletion add a further dimension to our appreciation of the complexity of the
information that has to be integrated to ensure the spatiotemporal regulation
of this myogenic determination gene. Furthermore, this analysis reveals
subpopulations of cells that contribute to myogenesis as the embryo
develops.
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MATERIALS AND METHODS |
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BAC transgene constructions
All BAC deletion constructs are based on BAC195APZ
(Carvajal et al., 2001a). For
BAC195
54-49, homology arms were synthesized by PCR amplification of
BAC195APZ with the following primer pairs: 5' homology arm
(1220 bp),
54-49.5F (5'-TTA GAT CTA TTG TCA GAA GAA TAG AGA AAA
GGA-3') and
54-49.5R (5'-AAG GAT CCG ATC TTG AAG AAA TTT
TGG TAA TTC C-3'); 3' homology arm (1209 bp),
54-49.3F
(5'-GTT TTG ATA GAG GAT GAA TAC TCA A-3') and
54-49.3R
(5'-TCA TTT GAA TAG AGA CCT AAA GAT C-3'). The 5' homology
arm fragment was cloned into pCRII (Invitrogen) to generate p
54-49.5.
The 3' homology arm fragment was digested with XhoII and cloned
into a BamHI-digested p
54-49.5 to give pCas
54-49.
For BAC19559-54, homology arms were synthesized by PCR amplification
of BAC195APZ with the following primer pairs: 5' homology arm
(140 bp),
59-54.5F (5'-CTG ATG CAT GCT TGT CAT GGT-3') and
59-54.5R (5'-TGG ATC CTG AAA ACG TGA GGC ACC GGA GG-3');
3' homology arm (140 bp),
59-54.3F (5'-CCA TAG GAA TTA CCA
AAA TTT CTT C-3') and
59-54.3R (5'-CGT AAA CCA TTA AGA TGG
TGG-3'). To generate the deletion cassette, 5' and 3'
homology arms were digested with BamHI and XhoII,
respectively, ligated and re-amplified using
59-54.5F and
59-54.3R.
For BAC19563-48, homology arms were synthesized by PCR amplification
of BAC195APZ with the following primer pairs: 5' homology arm
(145 bp),
63-48.5F (5'-AAA TGT GCT AAT GTG GAG AGG-3') and
63-48.5R (5'-CAC ATA CAC AAC TTC ACA AAA GCT ATG CCA GGT TGC TAT
CCC TCC-3', including a 24mer tail homologous to the 5'-end of the
3' homology arm); 3' homology arm (144 bp),
63-48.3F
(5'-AGC TTT TGT GAA GTT GTG TAT GTG-3') and
63-48.3R
(5'-GTC TGC ATG GAA CTA GTG TAA-3'). To generate the deletion
cassette, 5' and 3' homology arm fragments were gel purified,
mixed in a 1:1 ratio, denatured for 5 minutes at 95°C and left to
re-anneal at 37°C for 30 minutes. Standard PCR-mix, not including primers,
was added and the reaction incubated at 72°C for 30 minutes. The extended
products were then re-amplified by PCR using
63-48.5F and
63-48.3R.
For BAC19554-49, pCas
54-49 was digested with NotI to
excise the deletion cassette. Fragments were isolated by gel electrophoresis
and subcloned into a pSV-RecA vector
(Yang et al., 1997
), which had
been modified by introducing a single NotI site replacing the
SalI cloning site (D.C., J.J.C. and P.W.J.R., unpublished).
Generation of the deleted BAC with this plasmid construct was carried out as
previously described (Cox et al.,
2002
). For the generation of other BAC deletion constructs, we
used our own modification of the linear recombination method
(Lee et al., 2001
;
Swaminathan et al., 2001
).
BAC195
59-54 was generated by introducing the 5 kb deletion in
BAC195APZ, while BAC195
63-48 was generated by deleting the
entire region from BAC195
59-54.
For BAC19559-54 and BAC
63-48, 25 ng of DNA from each BAC was
used to transform electrocompetent E. coli DY380 cells. Single
colonies growing under chloramphenicol (CAM) selection were analysed to check
that BACs transferred to the new host were not rearranged. Single colonies
were isolated and grown on LB-CAM media overnight at 32°C with constant
agitation. This culture (220 µl) was used to seed 11 ml of LB-CAM. Cells
were incubated at 32°C with shaking (>250 rpm) until the
OD600 was between 0.5 and 0.7. Cultures were then incubated at
42°C for 15 minutes, transferred to wet ice and left to cool down for at
least 20 minutes. Cells were washed three times in ice-cold H2O and
electroporated immediately after the last wash. Deletion cassettes were
denatured by 10 minutes incubation in 300 mM NaOH, ethanol precipitated,
resuspended in 20 µl of cold H2O and mixed with the
electrocompetent DY380 cells carrying the BAC of interest. Electroporation
conditions were as follows: 1.75 kV, 200 Ohms, 25 µF. After
electroporation, cells were diluted and plated into a single 96-well plate at
a density of 10-30 cells/well. After overnight growth at 32°C, colony
pools were screened by PCR using primers outside the deletion cassette.
Positive pools were diluted and plated on LB-agar CAM to obtain
250
colonies/plate and incubated overnight at 32°C. Single colonies were
picked onto 96 well plates, grown overnight at 32°C with constant
agitation and PCR-screened with the same primer pair to identify positive
clones. All clones were sequenced to confirm the deletion, and the integrity
of the sequences corresponding to the homology arms. Furthermore, positive
clones were digested with a panel of restriction enzymes to ensure no
additional deletions, insertions or rearrangements had occurred.
Generation of transgenic mice
BAC DNA purification was carried out as described previously
(Carvajal et al., 2001a) and
plasmid fragments as described elsewhere
(Kelly et al., 1995
).
Transgenic mice were generated by microinjection of purified BAC or plasmid
DNA into fertilized (C57BL/6JxSJL) or (CBAxC57BL/6J) F2
eggs at a concentration of
1-2 ng/µl using standard techniques
(Hogan et al., 1994
). Injected
eggs were reimplanted the same day or the day after the injection into
pseudopregnant (C57BL/6J x CBA) F1 foster mothers.
Identification of transgenic animals
DNA was prepared from mouse tails or, for transient transgenics, a region
of the embryo, and analysed by PCR, using standard techniques.
Analysis of transgene expression
Heterozygous transgenic males were crossed with non-transgenic females
([C57BL/6JxSJL or C57BL/6JxCBA] F1). Embryos were
dated, taking E0.5 as the day of the appearance of the vaginal plug. Transient
transgenic embryos were dated taking the day of reimplantation into the
pseudo-pregnant foster mothers as E0.5. Numbers of positive transient
transgenics analysed at each time point are indicated in
Table 1. The following
transgenic lines, with numbers given in brackets, were also analysed:
-58/-48Myf5-nlacZ (2), BAC195Z (6), BAC195APZ (5),
BAC19563-48 (3), BAC195
59-54 (3) and
BAC195
54-49 (4). X-gal staining: embryos were dissected in PBS, fixed
in 4% paraformaldehyde for 5 to 60 minutes depending on the age of the embryo,
or in Mirsky's Fixative (National Diagnostics) for 1 hour to overnight, rinsed
twice in PBS and stained in X-gal solution
(Summerbell et al., 2000
;
Tajbakhsh et al., 1996a
) at
37°C from 2 hours to overnight. Transgenic embryos were examined by
whole-mount microscopy or cryostat sectioning, as described previously
(Kelly et al., 1995
).
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RESULTS |
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DISCUSSION |
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Myf5 expression in the limbs
Sequences within the -58/-48 kb region are essential for early expression
of Myf5 in limb buds. An element located between -57.5 kb and -57 kb
directs robust transcription of the nlacZ reporter to the fore- and
hindlimb buds, following the anteroposterior developmental gradient, in the
same spatiotemporal pattern as the endogenous gene. This 500 bp sequence,
which is conserved between human and mouse, is therefore a potential target of
signalling pathways/transcription factors responsible for the activation of
this myogenic determination gene once the muscle progenitor cells have
migrated from the somite to the limb bud. The same sequence also directs
activation of Myf5 transcription in the hypoglossal cord. This is yet
another example of multiple elements targeting the same site, because another
element that also directs expression to the hypoglossal cord is present in the
region between -81 kb and -63 kb (Carvajal
et al., 2001b) and is necessary in the context of the locus. Cells
of the hypoglossal cord also delaminate from the hypaxial dermomyotome of
occipital somites, but move as a coherent mass
(Noden, 1983
), with activation
of Myf5 before they attain their final location around the larynx or
in the tongue, where they contribute to the formation of skeletal muscle
(Mackenzie et al., 1998
). It
is therefore surprising that this different mode of myogenesis is activated by
the same element, and it remains to be seen if the same regulation is
involved. It is also striking that this element directs reporter gene
expression to the hypaxial somitic bud in the interlimb region, at a stage
when this is a remnant of the epithelial dermomyotome, which still harbours
myogenic progenitor cells that activate Myf5. This is in contrast to
cells of the hypoglossal cord and limb buds, which express Myf5 only
when they have left the somite.
A second element in the region between -53.3 kb and -48 kb also contributes
to Myf5 expression in the limb buds. This element is more active in
the hindlimb, where reporter gene expression is clearly observed in the
developing muscle masses at a time when ß-galactosidase activity is
barely detectable in the forelimb. Deletion of the region between -59 kb and
-54 kb, where the other limb element is located, confirmed this result.
Forelimb expression appears to be delayed and generally weaker, but seems to
extend to most of the muscle masses. This distinction between fore- and
hindlimbs is particularly interesting in view of the unexpected results of
mutations in the Lbx1 and Mox2 homeobox genes. Despite the
fact that they are present in myogenic cells in fore- and hindlimbs, the
absence of Lbx1 seriously compromises the formation of many forelimb muscles
(Brohmann et al., 2000;
Gross et al., 2000
;
Schafer and Braun, 1999
),
whereas mutations in Mox2 mutants mainly affect hindlimb muscles
(Mankoo et al., 1999
).
Recently, it has been shown that Tbx5 and Tbx4 genes are
expressed in fore- and hindlimbs, respectively
(Gibson-Brown et al., 1996
)
and required for their development
(Rodriguez-Esteban et al.,
1999
). Pitx1 (Logan
and Tabin, 1999
) is another example of a gene that plays a role in
hind- but not forelimb development. These mutant phenotypes point to
regulatory differences in the limb environment that the muscle progenitor
cells enter, in addition to potential intrinsic differences in fore- and
hindlimb progenitors themselves. Further analysis of the Myf5 limb
element at -53.3/-48 will provide more insight into the differences in the
regulatory programme between fore- and hindlimbs.
Deletion of the -58/-48 region, although demonstrating that it is required
for early expression of Myf5 in limb buds, also shows that by E12.5
other regulatory sequences begin to participate in Myf5 transcription
in the muscle masses of the limbs. This is an autonomous function and
therefore not simple maintenance, because it is initiated in the absence of
the -63/-48 region. All muscles appear labelled eventually by the BAC
transgene with this deletion, although initially this is more readily
detectable in proximal muscles. It may be associated with the initiation of
secondary myogenesis, which makes a major contribution to the growth of
differentiated limb muscles from about E14
(Ontell and Kozeka, 1984).
Myf5 expression in the somite
Several sites of myogenesis in the somite are targeted by the region
between -58 kb and -48 kb that, together with the previously identified early
epaxial enhancer (Teboul et al.,
2002), intragenic hypaxial enhancer
(Summerbell et al., 2000
),
upstream hypaxial sequence (Carvajal et
al., 2001a
) and myotome sequence present in the -23 kb region
(Hadchouel et al., 2000
),
constitute a set of regulatory modules that orchestrate Myf5
transcription in the somitic cells that form the myotome. Initially, the early
epaxial enhancer (Teboul et al.,
2002
) activates Myf5 transcription in the epaxial
dermomyotome, from which cells delaminate, and then, in the presence of Myf5,
become correctly positioned to form the epaxial myotome
(Tajbakhsh et al., 1996b
). A
second element contained in the -57.5/-56.6 region of the upstream enhancer
then activates Myf5 transcription in the epaxial myotome, which, as
the dermomyotome continues to grow in an epaxial direction
(Denetclaw and Ordahl, 2000
;
Spörle, 2001
) and to
produce myogenic precursors, becomes positioned more centrally, intercalated
between epaxial-most and hypaxial components of the myotome. It is here that
transcripts of Mrf4 and those for differentiation markers, such as
myosins (Lyons et al., 1990
;
Spörle, 2001
), are first
detected. Myf5 is required at this stage to activate Mrf4/myogenin
transcription. The -57.5/-57 kb fragment does not direct epaxial myotome
expression, indicating that the 400 bp at -57/-56.6 kb contains this
transcriptional module. This region is conserved between human and mouse
genomic DNA, in part because it also contains an exon of the Ptprq
gene (Carvajal et al., 2001a
).
Another regulatory element contained within -23 kb of Myf5 also
targets a subdomain of the epaxial myotome
(Hadchouel et al., 2000
).
The region between -53.3 kb and -48 kb also displays some somitic activity
in a subset of cells in a more hypaxial part of the myotome. Labelling is seen
at E11.5 in the most anterior somites and later in some muscles anterior to
the forelimb. At earlier stages of development, somitic labelling is only
occasionally seen. More extensive transgene expression in somites on the
anteroposterior axis is also sometimes seen, indicating that the -53.3/-48
region can potentially direct such transcription. In the deleted BACs, it is
difficult to distinguish the contribution of this region from that of the
intragenic hypaxial enhancer. The hypaxial enhancer, located within the
Myf5 gene (Summerbell et al.,
2000) directs transcription in the early hypaxial myotome, and
labels the caudal edge of the somite. This labelling, together with that due
to the early epaxial enhancer, is evident when the -63/-48 region is deleted
from BAC195APZ. A further hypaxial element is present in the 5'
region upstream of -88 kb (Carvajal et al.,
2001a
). As the somite matures, and the dermomyotome disintegrates,
epithelial structures, which probably continue to be sources of myogenic
progenitor cells, are retained at the epaxial and hypaxial extremities of the
somite. The 500 bp fragment at -57.5/-57 kb, which also directs Myf5
transcription in the limb buds, targets these sites. The fact that epaxial and
hypaxial extremities of the dermomyotome are targeted earlier by other
regulatory sequences, illustrates the combinatorial action of elements
directing the complete spatiotemporal expression of Myf5 in the
somite. At earlier stages of myogenesis, the somitic bud contributes to the
hypaxial myotome and then to the formation of body wall and intercostal
muscles. The behaviour and fate of cells in the later somitic bud can now be
examined by means of these regulatory elements. The same is true for the later
epaxial bud in relation to the contribution of the earlier epaxial
dermomyotome, targeted by the early epaxial enhancer
(Teboul et al., 2002
).
Analysis of transgenes which direct Myf5 transcription in the
somite would suggest that at least six and possibly eight different regulatory
modules are responsible for spatiotemporal aspects of this expression.
Presumably, this reflects the complexity of the signals that modulate the
construction of the myotome, from which all the different muscles of the trunk
originate. It probably also reflects the way in which the mammalian myotome
has evolved from the myotome of more primitive vertebrates, which prefigures
simpler epaxial/hypaxial muscle derivatives, as in the body of fish for
example. The analysis of Myf5 regulation in the zebrafish embryo
suggests that the proximal promoter region can direct somite expression
(Chen et al., 2001). The
-58/-48 enhancer region, together with the early epaxial and hypaxial
enhancers play a major role in the expression of Myf5 in the mouse
somite, whereas the proximal promoter itself appears to have little or no
regulatory capacity (Summerbell et al.,
2000
).
The way in which Myf5 regulation may have evolved is intimately
related to that of the Mrf4 gene, which is linked to it in the same
locus in all vertebrates examined (Braun et
al., 1990; Miner and Wold,
1990
). The expression profiles of these two myogenic factor genes
are distinct. Although Mrf4 appears to be regulated, in part, by
sequences immediately 5' to it
(Patapoutian et al., 1993
;
Pin et al., 1997
), it is also
dependent on sequences further upstream
(Carvajal et al., 2001a
); it
will be interesting to establish to what extent the -58/-48 kb enhancer region
interacts with the Mrf4 promoter, which lies 5' to that of
Myf5. Another myogenic factor gene, MyoD, which, like
Myf5, plays a role in skeletal muscle determination
(Rudnicki et al., 1993
), has a
distal enhancer that is located at -22 kb from the gene
(Goldhamer et al., 1995
). This
directs early expression at sites of muscle formation in the embryo, whereas
more proximal 5' elements are necessary for transcription at later
stages of skeletal muscle development. However, the MyoD enhancer,
which is also active in limb buds, hypoglossal cord and myotome, can be
reduced to a single 258 bp core element
(Goldhamer et al., 1995
;
Kucharczuk et al., 1999
), in
contrast to Myf5, where the -58/-48 kb enhancer region breaks down
into discrete elements that target different sites. Furthermore, as discussed
here, crucial elements that direct Myf5 expression in the embryo, as
well as during later stages of development, are present elsewhere in the
locus. These differences probably reflect the fact that MyoD lies
genetically downstream of Pax3 and Myf5, which govern the
entry of cells into the myogenic programme. Myf5 is therefore the
target of the signalling pathways that specify myogenic cell fate and that
differ between sites of muscle formation in the embryo, acting through
different Myf5 regulatory sequences. Although it was not surprising
that limb versus dermomyotome/myotome expression of Myf5 should be
subject to different controls, the analysis presented here reveals the
extraordinary complexity of myogenic patterning. At least three different
regulatory circuits govern Myf5 transcription in the limb, two in the
hypoglossal cord, two in the epaxial and three in the hypaxial dermomyotome,
and probably at least three more in the myotome. Other upstream regulatory
genes, which have partially overlapping patterns of expression, may well
display a similar complexity, such that small numbers of cells may read a
unique code specifying muscle fate. Such codes, which would determine the
myogenic body plan of a mouse, no doubt reflect the many ways in which further
cell populations were co-opted into the muscle programme as vertebrates
evolved and ever more sophisticated muscle functions were required.
Identification of multiple Myf5 regulatory elements now makes it
possible to dissect muscle formation at any one site, both in terms of
molecular regulation and of unique cellular contributions.
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ACKNOWLEDGMENTS |
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Footnotes |
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Present address: INSERM U36, Médecine Expérimentale,
Collège de France, 11 place Marcelin Berthelot, 75005 Paris Cedex 231,
France
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