1 National Centre for Biological Sciences, Tata Institute of Fundamental
Research, Bellary Road, Bangalore 560065, India
2 The Salk Institute Peptide Biology Lab, 10010 North Torrey Pines Road, La
Jolla, CA 92037, USA
3 Centro de Biologia Molecular "Severo Ochoa", UAM-CSIC, Madrid
28049, Spain
4 Department of Zoology, University of Cambridge, Downing Street, Cambridge CB2
3EJ, UK
* Authors for correspondence (e-mail: cmbate{at}ncbs.res.in and vijay{at}ncbs.res.in)
Accepted 20 April 2004
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SUMMARY |
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Key words: Myogenesis, Myotube, Muscle, Founder cell
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Introduction |
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We have examined the formation of multi-fibre muscles, i.e. muscles that
function together as a contractile unit, in the adult fly
(Fig. 1). In the mesothorax of
the adult, the most prominent muscles are the indirect flight muscles (IFMs),
whose development has been charted in some detail
(Fernandes et al., 1991;
Roy and VijayRaghavan, 1999
).
The IFMs consist of the dorsal longitudinal muscles (DLMs), an array of six
large fibres, and three groups of dorsoventral muscles: DVM-I (three fibres),
DVM-II (two fibres) and DVM-III (two fibres). The mesothorax contains another
large muscle, namely the tergal depressor of the trochanter (TDT) or jump
muscle, which consists of many fibres bundled together as a unit. The dorsal
thorax also contains the direct flight muscles (DFMs), involved in changing
the orientation of the wing. Each of these muscles is a multi-fibre
contractile unit. The muscles in the adult abdomen are also arranged as
well-defined sets of fibres, which form dorsally, laterally and ventrally in
each segment (Fig. 1)
(Currie and Bate, 1991
).
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Materials and methods |
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Heat shocks
We found that the rate of development at 22°C was 0.75 times that at
25°C, and that at 31.5°C was approximately 1.3 times that at 25°C
(Anant et al., 1998). Based on
this, 0-hour APF pupae were grown at 22°C for 21 hours and 20 minutes
(corresponding to 16 hours APF at 25°C), 24 hours (
18 hours at
25°C), 26 hours and 40 minutes (
20 hours APF at 25°C), 29 hours
and 20 minutes (
22 hours at 25°C), and then raised to 31.5°C
for 6 hours, 4 hours and 30 minutes, 3 hours, and 1 hour and 30 minutes,
respectively.
Tissue preparation
White prepupae (0-hour APF) were collected on moist filter paper in a Petri
dish and grown at 25°C for different intervals. For the GAL4-UAS crosses
and their controls, white prepupae were collected and grown at 29°C. The
pupal and larval tissues were prepared for immunohistochemistry as described
previously (Fernandes et al.,
1991). The pupal preparations were mounted in 70% glycerol for
X-GAL stained preparations, or in Vectashield mounting medium (Vector
Laboratories, Burlingame, CA) for fluorescently labeled preparations.
Immunohistochemistry
Anti-Ewg antibody raised in rabbit was used at a dilution of 1:500
(DeSimone et al., 1996).
Anti-ß-galactosidase monoclonal antibody and 22C10 (both from The
Developmental Studies Hybridoma Bank) were used at a dilution of 1:50.
Anti-Twist antibody, a gift from Siegfried Roth (University of Köln), was
used at a dilution of 1:500. Vestigial antibody was a gift from Sean Carroll
and was used at a dilution of 1:200. Anti-MHC antibody, a gift from Dan
Kiehart, was used at a dilution of 1:500. For double-antibody stained
preparations of 1151-GAL4, duf-lacZ; UASdnRac1/+ pupae
(Fig. 7A-E), pupae were
incubated first in anti-MHC antibody and developed in the absence of nickel
sulphate (giving a light brown colour), then incubated in
anti-ß-galactosidase and developed in the presence of nickel sulphate
(giving a black colour). For preparations stained both with X-GAL and antibody
(Fig. 7F-I), pupae were first
incubated overnight in X-GAL, then processed for antibody staining. DIC images
were taken using a Nikon Eclipse E1000 microscope. For fluorescent images,
secondary antibodies conjugated to Alexa Fluor dyes (from Molecular Probes,
Eugene, OR) were used: Alexa 488 for green labeling and Alexa 568 for red
labeling. Fluorescent preparations were scanned using the confocal microscope
(MRC-1024, BioRad Laboratories, Hercules, CA) and analyzed using Metamorph
(version 4.5, Universal Imaging).
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Results |
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These findings suggest that, just as in the embryo, the formation of
myotubes in the adult may be initiated by the selection of single founder
myoblasts that are identifiable by their expression of duf-lacZ.
Other myoblasts would be recruited to these founders and fuse with them and
(again, as in the embryo) these fusing cells would themselves be induced to
express duf-lacZ, albeit at a lower level. If this view of adult
fibre formation is correct, then it should be generally true for all cases in
the adult where fibres form de novo from groups of aggregating myoblasts. With
this in mind, we looked at the regular arrays of fibres that form dorsally and
laterally in the adult abdomen. There are many such fibres laid out in a
well-organized pattern and they are derived from myoblasts that, unlike the
DVM cells, come not from the discs but from pools of cells associated with the
abdominal nerves (Currie and Bate,
1991).
The formation of the syncitial muscles in the abdomen begins at about 28
hours APF (Currie and Bate,
1991). We looked at a stage prior to this to see whether single
duf-lacZ-expressing cells appear before fibres form. Once again, we
observed a striking correspondence between forming fibres and
duf-lacZ expression in the abdomen, with every fibre preceded by a
single duf-lacZ-expressing nucleus at the appropriate position. At 24
hours APF, we observe an array of duf-lacZ-expressing cells in each
of the dorsal hemisegments. One of the hemisegments (A4) is shown in
Fig. 3A. The monoclonal
antibody 22C10 also labels these cells
(Fig. 3B,C). By 28 hours APF,
these cells are in positions where the future muscle fibres will form
(Fig. 3D). By 50 hours APF,
when the formation of the syncitial fibres is largely complete, we observed
one nucleus in each fibre that expresses duf-lacZ at higher levels
than the rest (Fig. 3E). We
observe a similar pattern of duf-lacZ expression in the developing
lateral muscles. At positions where the future lateral muscles will form there
are single duflacZ-expressing cells that are also 22C10 positive
(Fig. 3F). These mononucleate
cells develop into multinucleate fibres (see
Fig. 3G,H), which each contain
several duf-lacZ-expressing nuclei.
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To show whether there is a similar division of myoblasts during adult
myogenesis, we generated a fusion-defective phenotype during adult myogenesis,
by overexpressing a dominant-negative form of the protein Rac1, a member of
the small GTPase superfamily involved in the process of fusion
(Paululat et al., 1999b).
Overexpression of the dominant-negative Rac1 (Rac1N17) in the embryonic
mesoderm severely delays the fusion process and results in abnormal fusion in
the later stages (Luo et al.,
1994
). We found that overexpression of Rac1N17 in the adult
myoblast pool severely reduces myoblast fusion, the effect being most dramatic
in the lateral muscles of the abdomen and, to a lesser extent, in the thoracic
muscles. Nevertheless, duflacZ-expressing myoblasts are present in
the correct number at the correct positions. Preparations of wild-type and
1151GAL4/UAS-Rac1N17 pupae are shown
(Fig. 7A,B). In the absence of
fusion, each putative founder cell begins to express myosin at the appropriate
stage, elongates and differentiates into a thin myotube. Two such lateral
founders (in different planes of focus) that have begun to extend processes
are shown in Fig. 7C-E.
Myoblasts that have failed to fuse cluster around the
duf-lacZ-expressing cells and, as in the embryo, express myosin, but
do not differentiate further (Fig.
7D,E). Wild-type lateral fibres with the founder nucleus in each
fibre expressing duf-lacZ are shown for comparison
(Fig. 7F). X-Gal staining does
not detect the low duf-lacZ expression in the remaining nuclei of
these fibres. But that these fibres are multinucleate is evident when observed
at a higher magnification (Fig.
7G,H). In the absence of fusion, the founders eventually develop
into mononucleate, myosin-expressing fibres
(Fig. 7I), like the
mononucleate muscles observed in the embryos of fusion mutants.
The putative founders of the DVMs in the thorax of 1151GAL4/UAS-Rac1N17 pupae are also present in a wild-type pattern and initiate fibre formation, as shown in Fig. 7K. Some fusion does occur, but to a lesser extent than normal. The DVM II fibres shown in Fig. 7K are not mononucleate but have fewer nuclei than wild-type fibres of the same stage (Fig. 7J). These fibres ultimately give rise to muscles, albeit thin, at the correct position and with the correct number of fibres (Fig. 7M). These results suggest that where myoblast fusion is prevented during adult myogenesis, a population of duf-lacZ-expressing myoblasts segregates normally, as in the embryo, and that, like the founders in the embryo, these cells uniquely have the capacity to complete differentiation to form muscles. They also demonstrate that, as in the embryo, by the onset of fibre formation adult myoblasts are of two classes: fusion-competent cells that do not express duflacZ and founders that do express duf-lacZ. It is these latter cells that have the capacity to complete myogenic differentiation even when fusion is blocked or reduced.
Selection of duf-lacZ-expressing founders is not mediated by lateral inhibition during adult myogenesis
In the Drosophila embryo, the diversification of muscle forming
mesoderm into founders and fusion-competent cells occurs through a process of
lateral inhibition mediated by Notch
(Corbin et al., 1991;
Carmena et al., 1995
;
Carmena et al., 1998
). As we
have now shown that single duf-lacZ-expressing cells are selected and
appear to act as founder myoblasts during adult myogenesis, it is important to
show whether, as in the embryo, a Notch-dependent lateral inhibition pathway
mediates this selection process. To test whether Notch has a function in
selecting specific myoblasts for duf-lacZ expression, we used a
dominant-negative and a constitutively active form of Notch. We reasoned that
if lateral inhibition were involved, then overexpression of a
dominant-negative form of Notch (dnNotch) in adult myoblasts would lead to an
increase in the number of duf-lacZ-expressing founders, whereas
overexpression of the active form (Nintra) should suppress duf-lacZ
expression altogether.
In fact, the results of these experiments appeared to be contradictory:
thus, expression of UAS-dnNotch caused no change in the number of DVM
founders (Fig. 8C) and flies of
the genotype 1151GAL4, UAS-dnNotch had the correct number of DLM and
DVM fibres (data not shown). We verified this conclusion by reducing Notch
function in two additional ways. We reduced function in the Notch signalling
pathway in myoblasts by overexpressing truncated forms of the protein
Mastermind (Mam), an essential component of the Notch signalling pathway. Mam
interacts with the intracellular domain of Notch and with Suppressor of
Hairless, and forms a transcriptional activation complex
(Wu et al., 2000;
Kitagawa et al., 2001
). Two
truncated versions of Mam, MamH and MamN, when overexpressed by the GAL4-UAS
system behave as dominant-negative proteins and elicit Notch loss-of-function
phenotypes (Helms et al.,
1999
). Overexpression of either UASMamN
(Fig. 8D) or UAS-MamH
(data not shown) in myoblasts using 1151-GAL4 had no effect on the
number of DVM founders. We further examined the role of Notch by
using a conditional allele, Nts1
(Shellenbarger and Mohler,
1975
). Because of the close proximity of the duf and
Notch loci, we could not generate duf-lacZ, Nts
recombinants and hence used 22C10 as the marker for founder cells in the
abdomen. The earliest time at which myoblasts expressing high levels of
duflacZ are also labeled with 22C10 is at 24 hours APF
(Fig. 3A-C). We removed Notch
function for different periods (2 hours, 4 hours, 6 hours and 8 hours) before
this stage by raising Nts animals to the non-permissive
temperature and looked at the number of 22C10-stained cells associated with
the abdominal nerves. The numbers of 22C10-expressing cells in the dorsal
(Fig. 8F) or lateral segments
(data not shown) of the abdomen were examined and shown to be unaffected in
these experiments. We know that all three approaches - using the
dominant-negative Notch or mastermind constructs, and using
Nts animals - are effective, as they all can reduce the
levels of Twist expression in adult myoblasts (data not shown), a known
consequence of Notch reduction in adult myoblasts
(Anant et al., 1998
).
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Discussion |
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An essential feature of embryonic myogenesis in the fly is the division of
muscle-forming mesoderm into myoblasts of two kinds: founders and
fusion-competent cells (Baylies et al.,
1998). During embryogenesis, fusion is an asymmetric process in
which founders and fusion-competent cells fuse with each other, but neither
class can fuse with itself. This ensures that, wherever a founder segregates,
it acts as a seed for the formation of a single myotube. During adult
myogenesis, groups of myoblasts aggregate to form muscles consisting of
multiple myotubes: our question is therefore, how does a fixed number of
myotubes arise from this aggregate? Is it by the formation of an appropriate
number of founder myoblasts and, if so, how is this controlled? Or is it by
some totally different process that might be of general relevance for the
formation of such multi-fibre aggregates?
Our results show that in the adult fly multi-fibre arrays arise by the choice of an appropriate number of founder cells, identifiable in the adult by the elevated expression of duf-lacZ.
A marker for embryonic founders is expressed during adult myogenesis
An earlier study of myogenesis in the adult thorax suggested on
morphological grounds that cells equivalent to founder myoblasts in the
Drosophila embryo were involved in the formation of at least three
muscles: the tergo-trochanteral (jump) muscle, and DVMs I and II
(Rivlin et al., 2000). In
addition Kozopas and Nusse showed duf-lacZ expression in one kind of
adult muscle, the developing direct flight muscles (DFMs), but did not examine
the function of these cells nor address the mechanisms by which they are
selected (Kozopas and Nusse,
2002
). We decided to extend these studies by looking, during adult
development, at the expression of a marker for embryonic founders,
duf-lacZ. By early pupal stages we were clearly able to identify
selective expression of duf-lacZ in both the thoracic and abdominal
myoblasts. Furthermore, in both cases the pattern of expression mirrored the
pattern of emerging fibres. Thus, where two or three fibres form, as in the
DVMs, we saw two or three duf-lacZ-expressing cells amongst the
aggregating myoblasts; where an array of fibres form, as in the lateral and
dorsal musculature of the abdomen, we saw an array of single cells expressing
the marker, prior to the formation of syncitial myotubes. We also saw that
these duf-lacZ-expressing cells were able to seed individual fibres
in the absence of fusion, or where fusion was severely reduced. These findings
emphasize not only the presence of a specialized class of myoblasts amongst
the adult muscle-forming cells, but suggest that these cells, one per fibre,
are the founder myoblasts. In addition, because of the known function of Duf
as an attractant for myoblasts (Ruiz-Gomez
et al., 2000
), it seems likely that the same patterns of
asymmetric gene expression that characterize founders and fusion-competent
cells prior to fusion in the embryo are recapitulated in the adult
muscle-forming population as syncitial myotubes are formed.
We were surprised to find that duf-lacZ is also expressed in what have previously been thought of as analogues of founders, namely the three persistent larval muscles that act as templates in each hemithorax, organizing the development of the large DLMs from the swarms of adult myoblasts that aggregate about them as metamorphosis begins. We assume that duf expression in these cells serves to attract the adult myoblasts to the templates, with which they then fuse to form the six fibres of the adult DLMs.
The onset of duf-lacZ expression in adult myoblasts
At the end of the third larval instar, duf-lacZ is detected at a
low level in most, if not all, adult myoblasts. This expression disappears and
is replaced by selective expression at a much higher level in the cells that
we identified as founder myoblasts, as we have described and discussed above.
We suspect that this initially uniform expression at a low level may reflect
the origins of the adult myoblasts from lineages that generate muscle founder
cells in the embryo. In those cases that have been studied in detail, it has
been shown that the pools of myoblasts from which adult myotubes will form,
arise from a small number of adult muscle precursor (AP) cells in the embryo.
In the case of the ventral abdominal muscle of the adult, for example, it can
be shown that, in each hemisegment, the pool of myoblasts that will generate
the several myotubes that make up this muscle are all derived from a single
ventral AP cell in the embryo (Ruiz-Gomez
and Bate, 1997) (reviewed by
Baylies et al., 1998
). This
cell in turn is the sibling of the founder myoblast that seeds the formation
of larval muscle VA3. This lineage is typical of the many muscle lineages that
generate muscle-forming cells in the embryo: the terminal division in each
lineage generates either two sibling founder myoblasts (e.g. VA1 and VA2), or
a founder and an adult precursor (VA3 and VAP). While the founders manifest
their muscle forming potential in the embryo, express duf-lacZ and
seed myotubes, the muscle-forming potential of the AP cells is suppressed.
These cells proliferate in the larva, and first differentiate during
metamorphosis as adult muscle formation begins in the pupa. Thus the adult
myoblasts are clonal descendants of single cells that are themselves the
products of founder myoblast-generating lineages in the embryo. We suggest
that in the hormonal environment of the third larval instar, aspects of the
founder lineage of these clones begin to be expressed. However, uniform
expression of duf-lacZ in a population of myoblasts has no apparent
functional sense. Therefore, the uniform pattern of expression (perhaps
reflecting the developmental history of the cells concerned) must be replaced
by local upregulation in a few cells that will act as founders and
downregulation in other myoblasts that will now respond to the localized Duf
signal. This is the sequence that we observe in both the abdomen and the
thorax, and we suggest that it is the control of this process that is decisive
for the formation of the correct pattern and number of myotubes.
Regulation of duf-lacZ expression in the adult myoblasts: the role of Notch-mediated lateral inhibition
Our experiments indicate that a lateral inhibition mechanism such as that
which leads to the segregation of muscle progenitor cells in the muscle
forming mesoderm of the embryo is not responsible for the later segregation of
duf-lacZ-expressing cells from among the adult myoblasts. For these
experiments, we focused our attention on the de novo segregation of the single
cells that appear to seed the formation of the DVM fibres. We found that if
Notch signalling is removed or blocked by the expression of dominant-negative
constructs in the adult myoblasts, there was no effect on the segregation of
an appropriate number of cells expressing duflacZ at the sites where
the DVM or abdominal fibres are formed. This is in stark contrast to the
effects of reduced levels of Notch in the embryo, which lead to an
overproduction of founder cells expressing duf-lacZ. However, the DVM
founder myoblasts are lost when Notch is constitutively active in the adult
myoblasts and this resembles effects seen in the embryo when Notch is
constitutively expressed. We suspect that this loss of adult founders reflects
an indirect effect of Notch, which, when activated, maintains twist
expression in the myoblasts concerned. We find that persistent expression of
twist alone blocks the appearance of founder myoblasts in the adult.
Our observations lead us to conclude that lateral inhibition mediated by Notch
is unlikely to be the mechanism underlying the segregation of the adult
founder myoblasts.
How is duf-lacZ expression regulated?
As lateral inhibition does not appear to select cells from the
muscle-forming population for duf-lacZ expression, we consider two
other putative sources of muscle patterning cues: the epidermal sites at which
individual muscle fibres will attach and the nerve fibres that will innervate
them. In the thorax, duflacZ expression in the larval templates for
the DLMs is first seen at the time stripe-expressing adult epidermal
cells (Lee et al., 1995;
Fernandes et al., 1996
) are
juxtaposed adjacent to the templates (A. Ghazi, unpublished). Preliminary
results indicate that reduction of the number of stripe-expressing
cells results in a reduction of duf-lacZ nuclei in the LOMs, and
increasing stripe expression increases duf-lacZ expression
(A. Ghazi, unpublished). The large number of stripe-expressing cells
that attach to each thoracic fibre make the decisive experiments (complete
removal of stripe-expressing tendon cell precursors and misexpression
of stripe in a large ectopic domain) difficult to perform. The role
of tendon cells, if any, in founder selection or duf expression may
have to wait for other approaches that shed light on the signalling pathways
involved.
Innervation might also play an important role in fibre formation through
the mediation of duf expression. Laser ablation experiments have
shown that DLMs can be formed even if the normal larval templates have been
ablated. However, if the larval templates and the innervation are both removed
then the DLMs fail to form (Fernandes and
Keshishian, 1998). This suggests that, where muscles form de novo,
innervation is an essential ingredient for the initiation of fibre formation
and may therefore play a role in the selection of duf-lacZ-expressing
founder myoblasts from the adult myoblast population. This view is reinforced
by the finding that, when there is no innervation, the DVMs, which normally
form de novo, do not develop at all
(Fernandes and Keshishian,
1998
). It is well known that innervation is essential for the
formation of the male specific muscle (MSM) in the abdomen
(Lawrence and Johnston, 1986
).
There is a close association between nerve fibre branches and forming muscle
fibres in the abdomen, and the MSM is itself a local aggregation of such
muscle fibres. Now that we have a marker that identifies the earliest stages
of fibre formation, we plan further experiments to investigate the part played
by innervation and attachment in selecting the cells that seed fibre
formation.
The broad conclusion is that an external cue from the region where the
muscle is destined to form is likely to set the number of contributing
myotubes [one external cue, Wingless, is required for maintenance of identity
of groups of myoblasts (Sudarsan et al.,
2001), but we have not yet established what external cues act to
select individual myoblasts from this pool]. In Drosophila, this
process seems to be mediated by the selection of duf-expressing
founder cells, each of which seeds the formation of a fibre. The number and
pattern of fibres could then be set by the strength and distribution of the
founder-inducing cue. We can envisage a similar process operating in
vertebrate myogenesis as myoblasts aggregate and fuse to form a pattern of
primary myotubes. Whether here too the patterning of fibres depends on the
induction of founder or seed myoblasts at sites of muscle formation is an
important question that remains to be resolved.
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ACKNOWLEDGMENTS |
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