Department of Cell and Molecular Biology, Technical University of Braunschweig, Spielmannstrasse 7, 38106 Braunschweig, Germany
* Author for correspondence (e-mail: h.arnold{at}tu-bs.de)
Accepted 15 April 2003
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SUMMARY |
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Our data suggest that the enhancer identified here collaborates with other somitic enhancers to ensure correct myotomal Myf5 expression. Moreover, it constitutes an important element that mediates somitic expression after the initial and transient Myf5 activation through a previously described sonic hedgehog-dependent early epaxial enhancer.
Key words: Myogenesis, Complex Myf5 regulation, Distal enhancers, Mouse
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INTRODUCTION |
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Genetic evidence argues that formation of myoblasts from myogenic precursor
cells in somites and prechordal mesoderm, and their successive differentiation
into muscle cells involve the expression of four myogenic regulatory factors
(MRFs): Myf5 (Braun et al.,
1989), myogenin (Edmondson and
Olson, 1989
; Wright et al.,
1989
), Mrf4 (Myf6 Mouse Genome Informatics)
(Braun et al., 1990
;
Miner and Wold, 1990
;
Rhodes and Konieczny, 1989
)
and MyoD (Myod1 Mouse Genome Informatics)
(Davis et al., 1987
). These
are members of the basic helix-loop-helix (bHLH) family of transcription
factors (reviewed by Arnold and Braun,
2000
). Myf5 is the first gene expressed in all muscle
progenitors, beginning in the DML of the dermomyotome, which rapidly generates
the epaxial myotome at E8.0 of mouse embryogenesis
(Ott et al., 1991
). Somewhat
later, Myf5 is also expressed in the hypaxial somitic domain
(Tajbakhsh et al., 1997
).
Expression of myogenin and Mrf4 in somites follows that of
Myf5 by 0.5 days and 1 day, respectively
(Bober et al., 1991
;
Sassoon et al., 1989
).
MyoD is also expressed in the myotome
2.5 days after the onset
of Myf5 expression (reviewed by
Buckingham, 1992
).
Interestingly, the migratory muscle precursors destined to the limbs do not
express Myf5 until premuscle masses have accumulated in limb buds.
Here and in head muscles, Myf5 expression is immediately followed by
MyoD transcription. In Myf5-deficient mouse embryos, myotome
formation is delayed until MyoD transcription begins independently of
Myf5, suggesting that Myf5 alone is essential for the formation of
the early myotome and the onset of myogenesis
(Braun et al., 1992
;
Braun et al., 1994
), whereas
MyoD appears to contribute to myogenesis in a separate, parallel pathway
(Rudnicki et al., 1992
).
Consequently, mice lacking both Myf5 and MyoD are unable to form myotomes and
muscle elsewhere (Rudnicki et al.,
1993
).
Activation of the myogenin gene apparently depends on the prior expression
of Myf5, as deduced from transgenic studies and the temporal order of
MRF expression in mouse embryos (Cheng et
al., 1993; Yee and Rigby,
1993
). These observations and those in other MRF-deficient mouse
mutants have led to the model that Myf5 and MyoD are
myogenic determination genes that are essential for the specification of
myogenic cell fate that act upstream of myogenin and possibly Mrf4, which both
seem to be involved in the terminal differentiation program
(Braun and Arnold, 1995
;
Venuti et al., 1995
).
Consistent with this view are observations that Myf5 and MyoD are capable of
remodeling chromatin and opening gene loci that participate in further muscle
differentiation (Bergstrom and Tapscott,
2001
; Gerber et al.,
1997
). Taken together, the demonstrated functions of Myf5
and its early expression prior to the other MRFs argue that, under normal
circumstances, Myf5 acts at the top of the myogenic cascade and
initiates myogenesis in vertebrates.
Activation of the myogenic determination gene Myf5 in the various
muscle-forming regions undoubtedly depends on multiple signals that have to be
integrated to regulate initiation and maintenance of transcription. Indeed,
control elements that mediate Myf5 gene regulation are beginning to
emerge. Using yeast artificial chromosomes (YACs) in chimeric mouse embryos,
we have shown previously that regulatory elements driving faithful
Myf5 expression in limb buds are located at least 45 kb upstream of
the transcription start site (Zweigerdt et
al., 1997). More recently, multiple proximal enhancer elements and
large, distantly located control regions for particular progenitor cell
populations in distinct myogenic locations have been identified in transgenic
mouse embryos (Carvajal et al.,
2001
; Gustafsson et al.,
2002
; Hadchouel et al.,
2000
; Summerbell et al.,
2000
; Teboul et al.,
2002
). Deletion series of YACs and bacterial artificial
chromosomes (BACs) carrying the Myf5/Mrf4 gene locus
demonstrated that most of the regulatory regions seem to function in a modular
fashion, each affecting specific aspects of the spatiotemporal expression
pattern of Myf5, emphasizing the enormous complexity of this
regulation (Carvajal et al.,
2001
; Hadchouel et al.,
2000
).
Based on plasmid-derived transgenes in mouse embryos, three distinct
enhancers have been found proximal to Myf5
(Summerbell et al., 2000). The
intragenic enhancer located within the transcribed sequence of Myf5
functions in the hypaxial domain of somites but drives reporter gene
expression incorrectly in the dermomyotome and in the posterior half of the
somites. A second enhancer in the intergenic region between Mrf4 and
Myf5 initiates transcription in muscle progenitors within branchial
arches that subsequently give rise to facial muscles
(Patapoutian et al., 1993
;
Summerbell et al., 2000
). A
third sequence, located 6.1 kb upstream of Myf5 and close to
Mrf4, directs early, transient expression in the epaxial dermomyotome
as a direct target of long-range sonic hedgehog (Shh) signaling
(Gustafsson et al., 2002
;
Teboul et al., 2002
). None of
these three regulatory elements, however, was capable of mediating
Myf5 activation in limb buds and maintaining it appropriately in the
other muscle-forming regions. Moreover, these enhancers failed to restrict
Myf5 expression to the myotomal compartment in somites, suggesting
that additional cis-acting elements were required to ensure accurate
Myf5 expression. In fact, sequences from 96 to 63 kb
upstream of the transcriptional start site were shown to be necessary for
later expression of Myf5 in head muscles and in a subset of
hypaxially derived trunk muscles
(Hadchouel et al., 2000
). This
element did not behave like a classical enhancer, because it failed to
function when linked directly to the Myf5 minimal promoter. Another element
required for Myf5 expression in the ventral domain of tail somites and the
most ventral component of thoracic somites was found to be located in the
region 140 to 88.2 kb
(Carvajal et al., 2001
).
Hadchouel et al. (Hadchouel et al.,
2000
) identified a 10 kb enhancer fragment 58/48
kilobases (kb) upstream of the Myf5 transcription start site that is
required for expression in limb muscles and also in somites. In the present
study, we particularly focused on further characterization of the
58/48 kb region of Myf5 and delineated key regulatory
cis-acting elements. Here, we report that a 270 bp core enhancer located
57 kb upstream of the Myf5 transcription start site is necessary
and sufficient to recapitulate the endogenous Myf5 expression pattern
in limbs and to maintain expression in somites. A second, closely spaced
enhancer element is essential to direct transgene expression in cervical
somites and to restrict transcription appropriately to the myotome. Thus, we
have identified two enhancer activities that profoundly affect the complex
regulation of Myf5 during myogenesis in somites and limbs.
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MATERIALS AND METHODS |
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Production of transgenic mice
Transgenic mice were generated by pronucleus injection of single-cell
embryos from ICR crosses as described (Yee
and Rigby, 1993). All constructs were analysed in multiple
transient transgenic embryos to ascertain statistical significance of the
observed expression patterns and filter out integration effects. Copy numbers
of integrated transgenes were determined at least once for each construct and
found to be in the range of two to ten, with no apparent correlation to
lacZ expression levels. Most embryos carrying a given construct
exhibited the same pattern and similar intensity of expression unless stated
otherwise in Table 1.
|
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RESULTS |
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Myf5-III fails to direct correct expression in myotomes and
limb buds, whereas Myf5-IV promotes it in both muscle-forming
regions
To further dissect the 58/53 region with respect to the
observed enhancer activities, the fragment was subdivided into a proximal 3 kb
(56/53) and a distal 2 kb (58/56) segment
represented by transgenes Myf5-III and Myf5-IV,
respectively. In addition to the expected activity in branchial arches,
transgenic animals obtained with Myf5-III exhibited strong ectopic
expression in the hypaxial dermomyotome with few positive cells in myotomes
between E9.5 and E13.5 (Fig.
4A-D). Cervical somites never expressed Myf5-III and the
initial activity in lumbar somites rapidly disappeared during embryonic
development, similar to the pattern obtained with Myf5-II
(Fig. 4B). Myf5-III
also entirely failed to direct Myf5 expression in limbs.
Occasionally, ectopic transgene activity was observed in head mesenchyme and
neural tube. These results strongly argued that the observed pattern was due
largely to the previously described branchial arch and intragenic
Myf5 enhancers (Patapoutian et
al., 1993; Summerbell et al.,
2000
). Apparently, the 3 kb fragment located 56 to
53 was unable to mediate normal Myf5 expression in somites and
limbs. However, in older embryos (E12.5/13.5), we consistently observed weak
transgene activity in proximal muscles at the bases of the fore- and
hindlimbs, probably in parts of the shoulder and hip musculature
(Fig. 4C,E). This then
suggested that the 56/53 sequence might exert limited enhancer
activity in a subset of proximal muscles in hip and shoulder girdles.
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DISCUSSION |
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To delineate these enhancer elements, we followed a gain-of-function
strategy by adding subfragments of the 10 kb distal region
(58/48) to the Myf5-promoter-driven lacZ
reporter gene. The Myf5 promoter including the branchial arch
enhancer and the additional intragenic somite enhancer were used to maintain
the natural gene context as closely as possible, and to facilitate comparison
of our data with those published previously using a similar promoter fragment
(Hadchouel et al., 2000). In
good agreement with these earlier reports, all of our transgenes that did not
receive enhancer activity by the added subfragments consistently exerted
expression in branchial arches and in the hypaxial dermomyotome that was
poorly maintained (Summerbell et al.,
2000
). However, some of the transgenes tested here exhibited
clearly different expression patterns, suggesting that the transcription
profile of the basal reporter construct was modified by enhancers presented by
the additional subfragments. In fact, most of the regulatory aspects of
Myf5 transcription during mouse embryogenesis appeared to be
recapitulated by the enhancer modules tested in our transgenes, with the
notable exception of the early epaxial expression and rather weak expression
in the hypaxial domain and the intercalated myotome. These observations are in
line with previous studies in which specific control regions for both the
early epaxial and the most-ventral somitic domains were identified in
different regions of the gene locus
(Carvajal et al., 2001
;
Gustafsson et al., 2002
;
Hadchouel et al., 2000
;
Teboul et al., 2002
). It is
interesting that the enhancers identified here contain two conspicuous
sequence elements that are highly conserved between mouse and human,
suggesting that at least some of the molecular mechanisms regulating the
murine Myf5 gene might also apply to the human gene.
Another consideration relates to the fact that the Mrf4 and
Myf5 genes in birds (Saitoh et
al., 1993), mouse (Patapoutian
et al., 1993
) and humans (Braun
et al., 1990
) have been conserved in close linkage but exhibit
different, albeit partially overlapping, spatiotemporal expression patterns.
Regulatory elements controlling both genes are interspersed throughout the
common gene locus (Carvajal et al.,
2001
), posing the problem of how enhancer elements distinguish
between the two promoters. We have not actually tested the effects of the
enhancers identified here on the Mrf4 promoter but, clearly, the limb
enhancer in its natural context does not lead to Mrf4 expression in
early limbs, despite the fact that it lies closer to the Mrf4 than to
the Myf5 gene. Presumably, insulator elements are required to shield
the Mrf4 promoter from the influence of this enhancer. Whether
somitic expression of Mrf4 is affected by the distal Myf5
enhancer cannot be evaluated by our experiments because the expression of both
genes overlaps in this compartment (Bober
et al., 1991
; Hinterberger et
al., 1991
). Preliminary observations, however, suggest that
Mrf4 expression in the myotome is controlled by elements that lie
much closer to its own promoter (M. Fomin and H.-H.A., unpublished). Further
investigations will be needed to elucidate the mechanisms underlying the
selectivity with which the various enhancers in the
Mrf4/Myf5 locus ensure specific regulation of both
promoters.
Sequence of 270 bp specifically drives Myf5 expression in
developing limb muscles
Our data clearly demonstrate that 270 bp of the H1 element, located around
57 kb upstream of the Myf5 transcriptional start site, are sufficient
to initiate robust transcription in the post-migratory muscle precursors in
fore- and hindlimbs, and presumably to maintain it in all developing flexor
and extensor muscles at least until E13.5. In addition, the H1 element also
contributes significantly to maintenance of expression in somites but lacks
the element to restrain dermomyotomal expression to the myotome and to ensure
accurate transcription in cervical somites. Although the limb-specific core
enhancer of Myf5 can be ascribed precisely to the first 270 bp of the
H1 sequence, the maintenance function has not been delineated so clearly. It
certainly overlaps with the limb enhancer but might extend into the second
half of H1, as suggested by the weak maintenance effect that we observed with
the transgene containing this sequence. Although published information and the
results presented here support the notion that the limb enhancer is unique and
solely responsible for Myf5 expression in limb muscles, a redundant
enhancer module cannot be ruled out completely. In fact, we consistently
observed weak expression in a subset of proximal limb muscles with transgenes
Myf5-III (56.2/52.8 kb) and Myf5-VIII. This
might point to proximodistal heterogeneity of muscles in the extremities or,
alternatively, might be the artefactual result of the ectopic expression in
the dermomyotome, which harbors migratory cells. Ectopic activity caused by
integration effects is unlikely because we observed this phenomenon in all
transient Myf5-III and Myf5-VIII embryos. Even if the limb
enhancer is not be unique within the Myf5 locus, it is certainly
sufficient to drive accurate expression in muscles of the fore- and
hindlimbs.
Little is known about specific signaling molecules that might induce
transcriptional activation of Myf5 in myoblasts that have entered the
limb buds, nor about how Myf5 expression is suppressed in the
migrating muscle progenitors. Clearly, Wnts, BMPs, FGFs and Shh are present in
limbs and might affect Myf5 expression. Moreover, calcineurin- and
NFAT-dependent signals were recently implicated in regulating Myf5
gene expression in skeletal muscle reserve cells
(Friday and Pavlath, 2001).
The identification of the limb core enhancer will facilitate investigation of
which, if any, of the signals are actually directly involved in the
transcriptional regulation of Myf5. Algorithms searching for binding
sites of transcription factors within the 270 bp core enhancer predicted many
potential consensus sequences including those for Lef1/TCF, Xvent1 and NFAT
binding, suggesting that Wnt, BMP and calcineurin-dependent signaling pathways
might actually play a direct role (H.-H.A. et al., unpublished). It is worth
mentioning that all transgenes containing the enhancer exhibited ectopic
expression in the notochord, a site of high Shh activity, which might suggest
that an element responsive to this signal is present. Mutational analysis of
potential binding sites is under way in order to clarify their roles and to
identify cognate transcription factors.
Combinatorial control of Myf5 expression in somites by
multiple enhancer modules
Comparing the expression patterns of Myf5-IV and
Myf5-VIII indicated that the enhancer activity for somitic expression
within the distal 10 kb region (58/-48) depended on the H1 element, at
least partly, and the H2 element, because separation of both conserved
sequences resulted in suboptimal enhancer activity. Thus, we have not
separated this enhancer physically from the limb enhancer and both might
indeed overlap. Timing and regionalization of Myf5 expression in
somites has turned out to be much more complex than anticipated. The distal
enhancer identified here contributes to this complexity in several ways.
First, it activates and maintains transgene expression in myotomes of
occipital/cervical somites, indicating a previously unrealized additional
control level of Myf5 expression along the anteroposterior axis. None
of the other regulatory regions examined in our transgenes promoted expression
in rostral somites, suggesting that the activity is unique to this enhancer.
The early epaxial enhancer also drives expression in cervical somites but it
does so only transiently in the DML and the early epaxial domain and not
within the myotome during the second phase of myogenesis
(Teboul et al., 2002). Second,
the distal enhancer directs expression of Myf5 to the myotome and
represses expression in the dermomyotome of all somites along the
anteroposterior axis. The ability to correct the ectopic dermomyotomal
expression associated with our transgene constructs, presumably through the
intragenic somite enhancer, is remarkable because it suggests that a
transcriptional silencer function in the dermomyotome is associated with this
region, in addition to the activation of transcription in myotomal cells.
Moreover, it argues for some kind of co-operativity between the different
regulatory modules controlling Myf5 expression in somites. It seems
likely, although it has not been proved experimentally, that the distal
enhancer described here is also responsible for the correction of the early
epaxial enhancer that drives ectopic dermomyotomal expression when tested in
isolation but not in the context of the entire locus
(Teboul et al., 2002
). Taken
together, our results thus provide evidence that the distal enhancer is
required and interacts with other somite enhancers (possibly the intragenic,
early epaxial and far-upstream hypaxial enhancers) to ensure correct
Myf5 expression in the myotome. Precise assessment of specific and
redundant roles of these enhancers in myogenesis must await their individual
deletion from the endogenous gene. This type of experiment will also provide
information about whether or not the distal myotomal enhancer affects the
somitic expression of Mrf4 as it does Myf5.
Specification of myogenic cell fate during skeletal myogenesis is the
result of signals from surrounding tissues
(Cossu et al., 1996).
Expression of Myf5 (and, later, MyoD) is required for the
acquisition of myogenic identity and might therefore be the first readout of
signaling pathways. Multiple candidates of signaling molecules for myogenic
cell specification and transcriptional activation of Myf5 have been
described, and control elements upon which signaling pathways might impinge
are beginning to emerge (for reviews, see
Buckingham, 2001
;
Cossu and Borello, 1999
;
Tajbakhsh and Buckingham,
2000
). Wnts (which emanate from dorsal neural tube and surface
ectoderm) and Shh (from the notochord and floorplate) have been identified as
positive signals for myogenesis in mouse and chicken
(Munsterberg et al., 1995
;
Stern et al., 1995
;
Tajbakhsh et al., 1998
),
whereas BMPs are thought to affect myogenesis and the expression of myogenic
determination genes negatively, and this activity is counteracted by BMP
antagonists like noggin or chordin produced in the dorsal midline, possibly in
response to Wnt signals (Pourquie et al.,
1996
). In Xenopus, Xmyf-5 expression in mesoderm can also
be activated by Wnt signals (Marom et al.,
1999
). More recently, a regulatory mosaic of repression and
activation involving Wnt and activin-like signals has been described to define
the Myf5 expression profile in the frog gastrula
(Yang et al., 2002
). A
requirement has been shown in mouse null mutants for Shh signaling during
initial Myf5 expression in the early epaxial somite
(Borycki et al., 1999
), and the
corresponding enhancer containing a Gli-binding-site has recently been
identified (Gustafsson et al.,
2002
). However, direct induction of Myf5 transcription by
Shh has been disputed by others (Kruger et
al., 2001
). Clearly, regulation of Myf5 must accommodate
the complex input of various signaling circuits, which might explain the
complexity of cis-acting control regions within this locus. The identification
of the enhancers described previously and in this report and their
delimitation to manageable size will now allow us to investigate the molecular
mechanisms underlying the recognition and integration of signals that
determine the complicated expression pattern of Myf5 in myotomes and
limb muscles.
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ACKNOWLEDGMENTS |
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