Biologie du Développement, UMR 7622, Université P. et M. Curie, 9 Quai Saint-Bernard, Bât. C, 6eE, Case 24, 75252 Paris Cedex 05, France
Author for correspondence (e-mail:
duprez{at}ccr.jussieu.fr)
Accepted 5 November 2003
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SUMMARY |
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Key words: Myf5, MyoD, Electroporation, Neural tube, Chick embryo
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Introduction |
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MRFs were discovered by their ability to convert various cell types into
differentiation-competent myogenic cells
(Weintraub et al., 1991). The
MRFs have been shown to activate directly the expression of muscle-specific
genes through interaction with E-box DNA-binding sites located in the
promotors of these genes. Some cell types are permissive for myogenic
conversion, while others are not
(Weintraub et al., 1989
). In
addition, in a subset of permissive cell types, forced expression of
MyoD is able to inhibit the ongoing differentiation program, in
addition to promoting the expression of the myofibrillar proteins. For
example, converted myosin-positive chondroblasts and RPE (retinal pigmented
epithelial) cells following retroviral infection by MyoD are negative
for cartilage-specific molecules and for melanin granules, respectively
(Choi et al., 1990
). However,
there is less information on the ability of the MRFs to initiate ectopic
myogenesis in vivo at ectopic sites in the embryo. Experiments expressing
Myf5 or MyoD at ectopic sites in Xenopus and mouse
embryos have shown that both Myf5 and MyoD can initiate expression of early
muscle differentiation markers (Hopwood
and Gurdon, 1990
; Hopwood et
al., 1991
; Frank and Harland,
1991
; Miner et al.,
1992
; Faerman et al.,
1993
; Santerre et al.,
1993
). According to these studies, forced expression of
Myf5 or MyoD does not induce the full set of markers,
reflecting muscle terminal differentiation, which consequently has led to the
general idea that Myf5 and MyoD have incomplete myogenic capabilities in vivo
(reviewed by Pownall et al.,
2002
). Nevertheless, there are two reports of muscle
differentiation in brain tissues: in Xenopus hindbrain after
injection of Xmyf5 or XmyoD into blastomeres of two- to
32-cell stage (Ludolph et al.,
1994
) and in the adult mouse brain of transgenic mice expressing
bovine Myf5 under the control of a viral promoter
(Santerre et al., 1993
).
However, in these studies, the ectodermal origin of the ectopic muscle cells
was not completely proved.
In this report, we investigate the consequences of forced expression of the mouse Myf5 and MyoD (Myod1 - Mouse Genome Informatics) genes in the chick neural tube, after electroporation. We show that ectopic mouse Myf5 and MyoD in the neural tube induces skeletal muscle differentiation in addition to inhibiting the neuronal differentiation program. This system allowed us to analyse, in an in vivo context, the transcriptional relationships between several factors known to be involved in myogenesis.
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Materials and methods |
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Construction of the recombinant expression vectors containing mouse Myf5 and MyoD
The complete mouse MyoD- and Myf5-coding sequences (a
gift from S. Tajbakhsh, Pasteur Institute, Paris) were inserted into the
pCAß expression vector, which contains the hybrid chicken ß-actin
promoter/CMV enhancer (Yaneza et al.,
2002). This hybrid promotor has been shown to drive efficiently
the expression of the inserted gene in chick neural tube
(Momose et al., 1999
;
Yaneza et al., 2002
;
Dubreuil et al., 2002
).
Electroporation in the neural tube
Embryos were co-electroporated with GFP/pCAß, a vector encoding
enhanced versions of green fluorescence protein that also served as control
(Momose et al., 1999), and
mouse Myf5/pCAß or mouse MyoD/pCAß. The recombinant expression
vectors were used at 1 to 4 µg/µl. The DNA was microinjected into the
lumen of the neural tube at the trunk level of HH13-14 (E2) chick embryos with
micropipettes. Electrodes were placed on either side of the embryos adjacent
to somites 10-20. A square-wave stimulator (AM-Systems) was used to deliver
five pulses of current at 35 volts for 50 ms each. With unilateral pulses,
only the right parts of neural tubes were transfected. Embryos were allowed to
develop at 38°C for 1-4 days, and processed for in situ hybridisation to
paraffin wax-embedded tissue sections.
In situ hybridisation to tissue sections and immunohistochemistry
Embryos were fixed and processed for in situ hybridisation to tissue
sections as previously described (Delfini
et al., 2000). The antisense digoxigenin-labelled mRNA probes,
were prepared as described: mouse MyoD and mouse Myf5, Myf5,
MyoD, Myogenin, Delta1, Serrate2, Notch1, Pax3
(Delfini et al., 2000
),
Paraxis (Delfini and Duprez,
2000
), FgfR4
(Edom-Vovard et al., 2001
) and
SCG10 (Stanke et al.,
1999
). The probes for Six1, Mox1, Mox2, Id2 originate
from the UMIST EST library (Boardman et
al., 2002
).
Differentiated muscle cells and neural crest cells were detected on sections by using the monoclonal antibodies MF20 and HNK1, respectively (Developmental Hybridoma Bank, University of Iowa). Axonal projections were recognised using the monoclonal antibody 3A10 recognising a neurofilament-associated antigen (Developmental Hybridoma Bank, University of Iowa). Immunohistochemistry were performed after the in situ hybridisation.
The regulation of each gene was tested on three to six embryos electroporated with mouse MyoD and on a minimum of two embryos electroporated with mouse Myf5, except for Mef2c (which was not tested after mouse Myf5 electroporation). For all probes, the multiple experiments gave consistent results (no regulation, down- or upregulation), showing 100% efficiency. Moreover, the mouse MyoD and Myf5 electroporated embryos always gave the same results, in term of the direction of regulation observed. The chick Myf5 and MyoD probes were tested on mouse tissue sections of E12.5 embryos and did not give any signals, excluding the problem of probe crossreaction between species.
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Results |
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Ectopic mouse Myf5 or MyoD in the neural tube leads to terminal muscle differentiation in neural tissues
In order to determine whether either mouse Myf5 or MyoD
were able to induce marked myogenesis in neural tissues, we performed
immunohistochemistry experiments with the MF20 antibody directed against
sarcomeric myosin heavy chains (MHC) after in situ hybridisation using the
mouse Myf5 or MyoD probes
(Fig. 2). Four days after
electroporation of either mouse Myf5
(Fig. 2A-C) or MyoD
(Fig. 2D-H), we can observe
MF20-positive cells in the neural tube
(Fig. 2D,G,H see also Figs
3,
4) and in the neural crest cell
derivatives (Fig. 2A-F). These
MF20-positive cells show the elongated aspect of skeletal muscle fibres. High
magnifications of these MF20-positive cells show striations reminiscent of the
classical sarcomeric organisation of normal muscle fibres, indicating that
terminal muscle differentiation has occurred in ectodermal tissue
(Fig. 2C,F,H). However, it is
not clear whether these MF20-positive cells are multinucleated. One
possibility (not exclusive with a multinucleated state) is that myosin
expression spreads in the axons of the neurons. It is noticeable that the
orientation of the MF20-positive cells can follow the path of the axons of
sensory neurons in the DRG, dorsal root ganglia
(Fig. 2D-F) or that of the
motoneuron axons (Fig. 2G,H).
MF20-positive cells can be observed transversally and longitudinally anywhere
along the dorsoventral axis of the neural tube. However, we never observed
MF20-positive cells in the proliferating ventricular zone, consistent with the
absence of ectopic mouse Myf5 or MyoD in this part of the
neural tube, 4 days after electroporation.
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Effects of forced-expression of either mouse Myf5 or MyoD on negative regulators of myogenesis
Notch signalling and the HLH transcription factor Id2 are thought to be
negative regulators of myogenesis. Overexpression of Id protein inhibits the
muscle differentiation program by association with E2A proteins in vivo
(Jen et al., 1992). Activation
of the Notch pathway inhibits myogenesis in the chick and Xenopus
embryos (Delfini et al., 2000
;
Hirsinger et al., 2001
; Kopan,
1994). We found that ectopic mouse MyoD
(Fig. 5A) or Myf5
(data not shown) does not upor downregulate Delta1 expression
(Fig. 5B). However, ectopic
mouse MyoD activates the expression of another Notch ligand,
Serrate2 (Fig. 5C).
The expression of the receptor Notch1 is also activated by ectopic
mouse MyoD (Fig. 5D),
reflecting an activation of Notch signalling
(Wilkinson et al., 1994
;
Lewis, 1996
;
Delfini et al., 2000
;
Hirsinger et al., 2001
).
Forced expression of either mouse Myf5 (data not shown) or
MyoD also activates the expression of Id2
(Fig. 5E,F).
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Discussion |
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The proliferating cells lining the lumen of the embryonic neural tube have
stem cell characteristics (Anderson,
2001). It is conceivable that the forced presence of mouse
Myf5 or MyoD in those cells triggers the muscle
differentiation program instead of the endogenous neuronal differentiation
program. Consistent with this hypothesis, we never observed coexistence of the
late neuronal differentiation markers and ectopic MRF.
bHLH transcription factors and their negative regulators
We have found that forced expression of mouse MyoD is able to
activate the expression of inhibitors of myogenesis, Id2 and Notch
components. The activation of Notch components by MyoD is also observed in the
Xenopus embryos, where XMyoD has been shown to activate the Notch
pathway, via its ligand Delta1
(Wittenberger et al., 1999).
This stimulation of myogenesis inhibitor transcription by MyoD is also
consistent with the large scale analysis of the genes regulated by MyoD in
10T1/2 cells, in which the mRNA levels of Notch signalling components and Id2
are increased (Bergstrom et al.,
2002
). This type of regulation reinforces the idea that the bHLH
factor MyoD uses the classic scheme of lateral inhibition for generating
muscle precursors. MyoD will trigger myogenic differentiation in some cells
and drive the activation of the Notch pathway in neighbouring cells, which
will in turn repress the expression and the activity of the bHLH gene,
stopping muscle differentiation in those cells. Consistent with this, forced
activation of the Notch signalling pathway (using the Delta1/RCAS virus)
inhibits MyoD expression in the chick limb and somite
(Delfini et al., 2000
;
Hirsinger et al., 2001
) and
interferes with MyoD activity (Kopan et
al., 1994
; Wilson-Rawls et
al., 1999
).
Notch components and Id proteins are general inhibitors of differentiation,
including neuronal differentiation. Id proteins are associated with neural
cell proliferation and inhibit differentiation in a variety of systems
(Martisen and Broner-Fraser et al., 1998;
Lyden et al., 1999;
Norton, 2000
). This activation
of myogenesis inhibitors by the myogenic bHLH factor, MyoD is to be related to
that of negative regulators of neurogenesis by the proneural bHLH genes, such
as neurogenins (Ngns) (Bertrand et al.,
2002
). Ngn2 activates the expression of Id2 in the chick
spinal cord (Dubreuil et al.,
2002
). The Ngns also activate the expression of Notch ligands,
which will then trigger the activation of Notch pathway
(Ma et al., 1996
;
Ma et al., 1998
;
Dubreuil et al., 2002
). This
property to induce differentiation and to generate supernumerary progenitors
through the canonical lateral inhibition mechanism seems to be a general
feature of bHLH factors. This general mechanism could provide an explanation
of why, in the competition between the (ectopic) muscle and (endogenous)
neuronal bHLH transcription factors, the myogenic factor is stronger than the
proneural gene in imposing its downstream differentiation program in the
neural tube context. First the expression MyoD, which is driven by an
artificial promoter leads to high levels of MyoD protein. In addition, the
activation of Notch signalling by the bHLH factors will be able to repress as
a feedback action the endogenous expression of proneural genes
(Ma et al., 1996
) but not that
of the transfected mouse MyoD driven by artificial promoters.
Interestingly, in a mesodermal context, retroviral misexpression of proneural
genes, such as Ngns, in the somites is sufficient to induce the ectopic
expression of SCG10, in addition to sensory-neuron-specific markers,
in dermomyotomes (Perez et al.,
1999
). However, this study did not analyse whether the endogenous
myogenic program was inhibited or co-existed with the ectopic neurogenic
program.
Reciprocal transcriptional regulations by the muscle factors and consequences for the involvement of Myf5 versus MyoD in myogenesis
We have shown that both mouse Myf5 and MyoD induce
ectopic expression of MyoD, but not that of Myf5, in the
chick neural tube. Although we cannot rule out completely the possibility that
chick Myf5 and MyoD (versus mouse) would activate the expression of endogenous
avian Myf5, these results are completely in line with those obtained
in Xenopus. Injection of XMyf5 and XMyoD activates
the transcription of the endogenous MyoD gene but not that of the
Myf5 gene in animal cap cells
(Hopwood et al., 1991). The
autoregulatory loop of MyoD is also observed in several mouse muscle
cell lines (Thayer et al.,
1989
; Braun et al.,
1989a
; Bergstrom et al.,
2002
). This is also in agreement with the fact that the DRR
enhancer of the MyoD gene contains conserved E-box binding sites and
thus may be a direct target of regulation by MyoD itself
(Kablar et al., 1997
;
Kablar et al., 1999
). The
absence of Myf5 activation either by itself or by MyoD has
also been noted in vitro (Braun et al.,
1989b
; Bergstrom et al.,
2002
). Both mouse Myf5 and MyoD lead to ectopic
expression of Myogenin in the chick neural tube, which is consistent
with Myogenin activation by Myf5 and MyoD in vitro
(Braun et al., 1989a
;
Braun et al., 1989b
;
Bergstrom et al., 2002
) and in
vivo (Miner et al., 1992
;
Santerre et al., 1993
), and
with mouse genetic studies that place Myogenin downstream of
Myf5 and MyoD (Hasty et
al., 1993
; Nabeshima et al.,
1993
).
Our in vivo results have several implications concerning the involvement of
Myf5 versus MyoD in myogenesis. First, they support the idea
that Myf5 is the first MRF to specify the skeletal muscle program in
vertebrates, MyoD having later function
(Tajbakhsh et al., 1997;
Tajbakhsh and Buckingham,
2000
; Delfini et al.,
2000
; Hirsinger et al.,
2001
). Another aspect of our results is that MyoD can
induce muscle differentiation in the absence of Myf5, Paraxis, Six1,
Mox1 and Mox2 in vivo, as the conversion of neural tissues into
skeletal muscle cells can occur in the absence of the corresponding
transcripts. This could be related to the block of muscle differentiation in
the absence of MyoD, despite the presence of Myf5, Pax3 and
Paraxis after Notch signalling activation in the chick somites and
limbs (Delfini et al., 2000
;
Hirsinger et al., 2001
). A
last aspect is that we never found any differences in terms of gene regulation
between Myf5 and MyoD. The fact that all the genes induced
by mouse MyoD are also induced by mouse Myf5 is expected, as
mouse Myf5 induces MyoD. However, the converse is not true.
We might expect to find genes only regulated by mouse Myf5, but we
have tested at least 20 genes without observing this cast.
In Xenopus, chick and mouse, Myf5 and MyoD
expression has been detected in non-muscle mesodermal tissues. In
Xenopus, ventral (nonsomitic) mesoderm transiently expresses
MyoD during gastrulation (Frank
and Harland, 1991). Myf5 transcripts also have been
detected at low levels in presegmental mesoderm in chick
(Kiefer and Hauschka, 2001
;
Hirsinger et al., 2001
) and in
mouse (Gerhart et al., 2000
)
embryos, suggesting the existence of inhibitory mechanisms of protein
translation or activity. In relation to this, it is important to realise that,
even in vitro, the myogenic conversion property of the MRF can only occur
after growth factor depletion (Weintraub
et al., 1989
; Yutzey et al.,
1990
), showing the importance of inhibitory mechanisms in muscle
differentiation. Myf5 transcripts have also been detected in the
neural tube (Tajbakhsh et al.,
1994
) and specific neurons of the brain
(Tajbakhsh and Buckingham,
1995
; Daubas et al.,
2000
). However, in this latter instance, the Myf5 protein is not
produced, providing evidence for post-transcriptional control mechanisms for
Myf5 in the mouse brain (Daubas et al.,
2000
). If such post-transcriptional regulation exists in the
neural tube, it is not strong enough to block the protein synthesis of the
ectopic MRF or, alternatively, the recombinant constructions do not contain
the regulatory sequences necessary to respond to such a signal.
Crosstalk between MyoD and FgfR4 during myogenesis
The observation of FgfR4 induction in the neural tube after forced
expression of MyoD indicates the existence of an unexpected positive
feedback loop from MyoD to FgfR4 during myogenesis. This
FgfR4 upregulation by MyoD is consistent with that observed in human
cells (S. J. Tapscott, personal communication). The upregulation of
FgfR4 observed 3 hours after electroporation supports the idea of a
direct regulation. Although the FgfR4 mutant mice are not very
informative (Weinstein et al.,
1998), the fact that in the chick limb FgfR4 transcripts
are detected before those of MyoD
(Marcelle et al., 1995
) and
that inhibition of FgfR4 signalling leads to a downregulation of MyoD
expression (Marics et al.,
2002
), clearly places FgfR4 as acting upstream of
MyoD. However, the precise role of FgfR4 in myogenesis is
not completely clear. FgfR4 transcripts are unambiguously detected in
mononucleated cells surrounding the muscle fibres (Marcelle et al., 1994;
Edom-Vovard et al., 2001
) and
FgfR4 downregulation is concomitant with terminal differentiation in
muscle cell lines (Halevy et al.,
1994
), indicating a role in myoblast proliferation of this
signalling pathway (Marcelle et al.,
1995
). However, inhibition of FgfR4 signalling seems not to modify
cell proliferation in the chick limb, suggesting instead a role in muscle
differentiation (Marics et al.,
2002
). The existence of a feedback loop from MyoD to
FgfR4 could highlight a dual action of FgfR4 signalling pathway in
myogenesis. In the chick limb at stage HH22/23, FgfR4 transcripts
present an expression domain similar to that of Myf5 compared with
the restricted MyoD domain
(Delfini et al., 2000
) (data
not shown). In the limb muscle masses we can distinguish a FgfR4- and
Myf5-positive domain close to the ectoderm and a more central domain
positive for FgfR4, Myf5 and MyoD. One hypothesis is that
low levels of FgfR4 signal would allow myoblast proliferation in the
Myf5 domain of the muscle masses, while high levels (induced by MyoD)
could initiate muscle differentiation in the MyoD domain. This
hypothesis could be related to the biphasic regulation of FgfR4
expression by different concentrations of Fgfs in muscle cell lines; this
differential expression of FgfR4 is correlated with the state of
muscle differentiation of the cells
(Halevy et al., 1994
;
Pizette et al., 1996
).
Interestingly, in the somites, FgfR4 transcripts display two distinct
domains of expression. FgfR4 transcripts are located along the
rostral and caudal edges of the dermomyotomes in mitotically active cells that
do not express MyoD (Kahane et
al., 2001
). In a second domain, FgfR4 transcripts are
also co-localised with those of Myf5 and MyoD in the
sublipdomain, an area subjacent at the dermomyotomal lips, which exhibits
intermediary properties between dermomyotome and myotome
(Cinnamon et al., 2001
).
In conclusion, we have shown that either mouse Myf5 or MyoD is able to induce muscle differentiation in neural tissues at the expense of the endogenous neuronal differentiation program. This provides an in vivo system, in which to study regulation between muscle factors in the absence of the classical muscle molecular context.
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ACKNOWLEDGMENTS |
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Footnotes |
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