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First published online 5 November 2008
doi: 10.1242/dev.027789
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Research Report |
ICREA and Institute for Research in Biomedicine (IRB), Parc Científic de Barcelona, Baldiri Reixac 10, 08028 Barcelona, Spain.
* Author for correspondence (e-mail: marco.milan{at}irbbarcelona.org)
Accepted 21 October 2008
SUMMARY
During the development of a given organ, tissue growth and fate specification are simultaneously controlled by the activity of a discrete number of signalling molecules. Here, we report that these two processes are extraordinarily coordinated in the Drosophila wing primordium, which extensively proliferates during larval development to give rise to the dorsal thoracic body wall and the adult wing. The developmental decision between wing and body wall is defined by the opposing activities of two secreted signalling molecules, Wingless and the EGF receptor ligand Vein. Notch signalling is involved in the determination of a variety of cell fates, including growth and cell survival. We present evidence that growth of the wing primordium mediated by the activity of Notch is required for wing fate specification. Our data indicate that tissue size modulates the activity range of the signalling molecules Wingless and Vein. These results highlight a crucial role of Notch in linking proliferation and fate specification in the developing wing primordium.
Key words: Notch, Wingless, EGF receptor, Wing imaginal disc
INTRODUCTION
Growth and fate specification of a given organ are two regulated processes
that have to be tightly coupled to generate a correctly shaped and sized
structure (Lecuit and Le Goff,
2007
). Uncoupling these two processes has disastrous consequences
in development and disease. In the past few years, much has been learnt about
the regulation of growth and fate specification. However, very little is known
about how these processes are coupled. The Drosophila wing imaginal
disc provides a well-studied model system for analyzing at a genetic, cellular
and molecular level these processes during development
(Cohen, 1993).
The wing primordium contains the progenitors of both the adult body wall
and the wing (Bryant, 1975).
The developmental decision between wing and body wall is made early in
development and is defined by the opposing activities of two secreted
signalling molecules, Wingless (Wg) and the EGFR ligand Vein (Vn), in the most
ventral and dorsal sides of the wing primordium, respectively
(Ng et al., 1996;
Wang et al., 2000;
Zecca and Struhl, 2002).
Genetic manipulations that increase Notch activity or activate Notch at
ectopic sites result in increased growth, and also in cancer
(Ferres-Marco et al., 2006;
Moberg et al., 2005;
Radtke and Raj, 2003;
Thompson et al., 2005;
Vaccari and Bilder, 2005).
Here, we present evidence that growth of the early wing primordium mediated by
the activity of Notch modulates the cellular response to Wingless and
facilitates wing fate specification.
MATERIALS AND METHODS
Drosophila strains
UAS-NdsRNA
(Presente et al., 2002);
UAS-notum (Giraldez et al.,
2002); UAS-SerTM and UAS-DlTM
(Herranz et al., 2006);
UAS-cycD UAS-cdk4 (Datar et al.,
2000; Meyer et al.,
2000); UAS-dmyc
(Johnston et al., 1999);
UAS-hippo (Harvey et al.,
2003; Wu et al.,
2003); UAS-PTEN
(Goberdhan et al., 1999).
Other stocks are described in FlyBase
(http://flybase.org/).
Antibodies
Mouse anti-Wg (4D4, Developmental Hybridoma Bank); mouse anti-Nubbin
(Ng et al., 1995); rat
anti-Hth (Wu and Cohen, 1999).
Other antibodies used are commercially available.
BrdU incorporation and tissue size measurements
Flies were allowed to lay eggs for 12 hours. Larval size was used to select
the same developmental stage in all genotypes analyzed. The number of
BrdU-labeled cells was counted in wild-type, sd-gal4; UAS-SerTM
and sd-gal4; UAS-SerTM; UAS-CycE early second instar wing discs
(48 hours after egg laying) that had been raised in the same conditions and
dissected simultaneously. BrdU staining was performed as described by Milan et
al. (Milan et al., 1996).
Using Image J software, the area of these discs was also measured. The area of
the sd-gal4; UAS-SerTM and sd-gal4; UAS-SerTM;
UAS-CycE discs were always compared with wild-type discs raised in the
same conditions. Final area measurements were normalized to the wild-type ones
and are presented in arbitrary units. Using Microsoft-Excel Software, the
average size and standard deviation of wing discs were calculated, and
t-test analysis was carried out.
Temperature shifts
We used the Gal4/UAS system (Brand and
Perrimon, 1993) combined with the thermo-sensitive version of
Gal80 [Gal80ts (McGuire et al.,
2004)], a repressor of Gal4 protein activity, to precisely
control, in time and space, gene expression. Adult flies carrying a Gal4
driver, the Gal80ts construct and an UAS-transgene were allowed to
lay eggs over a period of 24 hours at 18°C. The progeny were then raised
at 18°C to maintain the Gal4/UAS system in a switched-off state but
transferred to 29°C for different periods of time during larval
development to induce Gal4/UAS-dependent gene expression.
RESULTS AND DISCUSSION
Early requirement of Notch in wing fate specification
During the second larval stage, the antagonistic activities of Wg and Vn
specify wing versus body wall fate. Notch activity has been proposed to have a
role in this process because the loss of Notch during this developmental stage
leads to a failure in the induction of wing fate with a concomitant
duplication of body wall structures (Couso
and Martinez Arias, 1994). We decided to further analyze the role
of Notch in this process, not only in the adult fly, but also in the
developing wing primordium, by using the corresponding wing and body wall
molecular markers.
We first blocked the activity of Notch and analyzed the resulting adult
flies (Fig. 1). To block Notch,
we expressed either dominant-negative forms of the Notch ligands Delta and
Serrate [DlTM and SerTM, intracellular deletions of Delta and
Serrate well known to repress Notch activity
(Sun and Artavanis-Tsakonas,
1996)], or a Notch RNA interference construct
[NdsRNA, known to reduce Notch protein levels and to lead
to strong Notch loss-of-function phenotypes in Drosophila tissues
(Presente et al., 2002)] (see
Fig. S1 in the supplementary material). We used the scalloped-Gal4
(sd-Gal4) driver because it is expressed in the wing disc from early
larval stages (Fig. 1C). The
expression of sd-Gal4 in early wing discs was not affected in
conditions of reduced Notch activity (see Fig. S2 in the supplementary
material). In adult flies, wings were either vestigial or absent (data not
shown), and body wall structures were often duplicated
(Fig. 1E,G,J). In the
developing wing imaginal disc, expression of the homeodomain protein
Homothorax (Hth) and the zinc-finger transcription factor Teashirt (Tsh) was
restricted to the presumptive body wall, while the homeodomain protein Nubbin
(Nub) was expressed in the presumptive wing territory
(Ng et al., 1996;
Wu and Cohen, 2002)
(Fig. 1A). Wg was expressed in
the body wall and wing territories of late third instar discs in a
characteristic pattern (Fig.
1A). We then analyzed and compared the expression of these
molecular markers in mature wing discs in which Notch activity had been
compromised. Nub was absent, and the characteristic expression of Hth, Tsh and
Wg in the notum showed a mirror-image duplication
(Fig. 1D,F). The characteristic
expression pattern of sd-Gal4 in the resulting late third instar wing
discs also showed mirror-image duplication (see Fig. S2 in the supplementary
material). These results confirm the requirement for Notch in wing fate
specification.
|
).
Notch acts upstream of Wg in wing fate specification
Similar defects in wing fate specification were obtained when the activity
of Wg protein (by overexpression of the Wg antagonist Notum) or its signalling
pathway (by overexpression of the antagonist of the Wg pathway, the kinase
Shaggy/Gsk3) were compromised in the sd domain
(Fig. 1H-J; data not shown)
(Giraldez et al., 2002;
Morata and Lawrence, 1977;
Sharma and Chopra, 1976), or
when a temperature-sensitive mutant allele of wg was used to block
its function for a period of 24 hours during the second instar
(Couso and Martinez Arias,
1994). Thus, Notch might either control the expression or activity
of Wg, or collaborate with the Wg pathway during wing fate specification.
Consistent with this, reducing the amount of Wg protein, in a wg
heterozygous background, increased the frequency of duplicated nota
(Fig. 2L). However, only in the
case of collaboration between Notch and Wg pathways might Notch be required in
a cell-autonomous manner. Therefore, to choose between these two alternatives,
we decided to block the Notch or Wg signalling pathways in a subset of cells
within the presumptive wing primodium and examine the expression of Nub.
Unfortunately, classical clonal analysis cannot be used to address this issue,
as clones of cells lacking Notch or Wg activity cannot be recovered in the
wing primordium, probably because of impaired cell proliferation or viability
(de Celis and Garcia Bellido,
1994; Giraldez and Cohen,
2003; Johnston and Sanders,
2003). For this reason, we decided to use the Gal4/UAS system to
compromise Notch activity in discrete territories within the wing primordium.
Blocking Notch activity in a stripe along the anteroposterior compartment
boundary (in patched-Gal4; UAS-NdsRNA larvae) or
throughout the dorsal compartment (in apterous-Gal4;
UAS-NdsRNA larvae) did not result in the loss of Nub
expression (Fig. 2A,C). By
contrast, blocking the response to Wg by the overexpression of Axin or
Shaggy/Gsk3 [two antagonists of the Wg pathway
(Logan and Nusse, 2004)] in
the same domains induced the loss of Nub expression in the anterior
(Fig. 2B; data not shown) or
dorsal (Fig. 2D) compartments.
These results indicate that Wg signalling is required in a cell-autonomous
manner to induce wing fate specification, as previously shown
(Ng et al., 1996). By
contrast, the requirement of Notch signalling in this process is not
cell-autonomous and it might be mediated by the activity of Wg. Indeed,
epistatic analysis confirmed this hypothesis. The expression of Wg ligand or
the activation of the Wg pathway in wing discs in which Notch activity had
been compromised rescued Nub expression
(Fig. 2E,F) and adult wing
specification (Fig. 2G). By
contrast, activation of the Notch pathway in wing discs in which Wg activity
had been compromised did not rescue the expression of this protein
(Fig. 2H,I), nor adult wing
specification (data not shown).
|
). Blocking
Notch activity in these cells throughout development (in patched-Gal4;
UAS-NdsRNA larvae) did not result in the loss of Nub
expression (Fig. 2A), and Wg
expression was not affected in early wing discs in which Notch activity had
been compromised (in sd>SerTM larvae,
Fig. 2K). Wg is required to
repress Vn expression in the most dorsal region of the early disc
(Wang et al., 2000). Vn
antagonizes wing development and specifies body wall fate. An alternative
mechanism by which Notch might affect Wg activity would be by interfering with
the ability of Wg to repress Vn expression. Indeed, we noted that reducing the
amount of Vn protein, in a vn heterozygous background, decreased the
frequency of duplicated nota caused by compromised Notch activity
(Fig. 2L). However, Vn
expression was not affected by blocking Notch activity (compare Fig.
2J and
2K). Taken together, these
results indicate that Notch activity is required upstream of Wg in the process
of wing fate specification, but that Notch does not regulate the relative
expression patterns of Wg and Vn.
|
), and growth induced by Notch is required for specification
of the eye within the Drosophila eye-antenna primordium
(Kenyon et al., 2003). We
therefore hypothesized that the requirement of Notch in wing fate
specification is because of its control of tissue growth. We first measured the size and analyzed the proliferation dynamics of early second instar wing discs after blocking Notch activity. Early second instar wing discs expressing the dominant-negative form of Serrate (SerTM) in the sd-Gal4 domain were on average 34% smaller than were wild-type primordia raised in the same conditions (Fig. 3I). The average wing disc sizes, in arbitrary units, were 1±0.3 (wild type) and 0.67±0.14 (sd>SerTM; number of scored discs: wild type, n=22; sd>SerTM n=40; P<10-6). The number of cycling cells, monitored by BrdU incorporation, was also reduced. The number of BrdU-positive cells in wild type and sd>SerTM wing discs was 14±4 and 6±1, respectively (wild type, n=7; sd>SerTM, n=11).
We next tested whether overexpressed cell cycle regulators or growth
promoters were able to rescue tissue growth and wing fate specification in
conditions of reduced Notch activity. Overexpression of cell cycle regulator
Cyclin E [which drives G1-S transition
(Neufeld et al., 1998)] in
wing discs in which Notch activity had been compromised was able to restore
the size of the wing primordia (Fig.
3I). The average size of sd>SerTM,CycE discs
(1.13±0.36, n=21) was significantly bigger than that of
sd>SerTM discs (0.67±0.14, n=40,
P<10-8) grown in the same conditions. Similarly, the
number of proliferating cells was also restored (an average of 13±3
BrdU-positive cells, n=7 discs). Interestingly, Nub expression
(Fig. 3A,C) and adult wing
specification (Fig. 3B,D,J)
were restored in these conditions (in sd>SerTM,CycE larvae
and flies). Cyclin E did not show this capacity in the absence of Wg activity
(Fig. 3E,F). Consistent with
this, the size of the wing discs was not reduced after blocking Wg activity
(the average wing disc sizes were 1±0.3 for wild type and
1.04±0.2 for sd>notum; P=0.77; n=8 and 5
discs, respectively). Adult fate specification was also rescued when the cell
cycle regulator String [previously known as Dcdc25, which drives G2-M
transition (Neufeld et al.,
1998)] was expressed in conditions of reduced Notch activity
(Fig. 3J). It is interesting to
note that, in late third instar wing discs, overexpression of CycE and String
has been reported to drive G1-S and G2-M transitions without causing any
increase in tissue size (Neufeld et al.,
1998). We therefore wondered whether the overexpression of these
cell cycle regulators was able to induce tissue growth in second instar discs.
Interestingly, the average size of sd>CycE (1.7±0.4,
n=39) and sd>Stg (1.13±0.22, n=33) early
second instar wing discs was significantly bigger than that of wild-type
(1±0.22, n=47) discs grown in the same conditions
(P<10-13 and P=0.01, respectively; see Fig. S3
in the supplementary material). These results suggest that the ability of CycE
and String to rescue wing fate specification is a consequence of increased
tissue growth. Alternatively, the increased cell cycling caused by these cell
cycle regulators might interfere with the ability of the cells to transduce
Notch signalling. We therefore analyzed the ability of SerTM to
block Notch signalling in the presence of high levels of CycE or String.
Similarly, we analyzed the ability of a dominantly active form of the Notch
receptor [Nintra (Struhl and
Adachi, 1998)] to activate the expression of Notch target genes in
the presence of high levels of CycE or String. As shown in Fig. S4 (see
supplementary material), the activity of the Notch pathway is not affected by
the overexpression of these cell cycle regulators.
|
), or dMyc
(Dm - FlyBase) (Johnston et al.,
1999), were also able to rescue wing fate specification under
conditions of reduced Notch activity (Fig.
3J). Conversely, expression of the growth repressor PTEN
(Goberdhan et al., 1999)
increased the frequency of duplicated nota under conditions of reduced Notch
activity (Fig. 3J), and
blocking growth by means of overexpression of the tumor suppressor gene
hippo (Harvey et al.,
2003; Wu et al.,
2003) in the early wing primordium induced failure in wing fate
specification with a concomitant duplication of body wall structures
(Fig. 3G,H). Taken together,
these results indicate that growth induced by Notch activity is essential for
the Wg-dependent induction of wing fate.
Concluding remarks
The expression of Wg in the most ventral part of the wing disc specifies
the wing field at the same time as restricting Vn expression to the most
dorsal part (Fig. 4A). Vn is
required to block the responsiveness of body wall cells to Wg. Thus, the
relative concentration of the diffusible proteins Wg and Vn
(Neumann and Cohen, 1997;
Schnepp et al., 1996;
Zecca et al., 1996)
experienced by disc cells directs their wing versus body wall fate. It is
interesting to note that the expression of these two molecules is established
long before the wing field is induced in the presumptive wing primordium
(Wu and Cohen, 2002). Wg
expression starts long before wing field specification takes place, as
revealed by the later induction of Nub expression and the reduction in the
expression of the body wall cell marker Tsh
(Fig. 4D-G). We therefore
propose that tissue growth modulates the cellular response to these signalling
molecules and controls, in time, wing fate specification. In the early wing
primordium, Vn might reach every wing cell, thereby blocking responsiveness to
Wg and repressing wing fate specification. Growth induced by Notch activity
might pull the sources of Wg and Vn apart and, thus, most ventral cells might
not sense sufficient Vn levels, so Wg would be able to induce wing fate.
Interestingly, the overexpression of Wg or overactivation of its signalling
pathway is able to bypass the requirement of growth in this process
(Fig. 2E,F), which indicates
that the cells sense the relative levels of Wg and Vn. Once the wing field has
been specified, Wg starts to be expressed along the presumptive wing margin,
where it exerts a fundamental function in the maintenance of the
Notch-dependent organizing center along the DV boundary
(Buceta et al., 2007;
Couso et al., 1994;
Rulifson and Blair, 1995).
Note that the organizing activity of Notch at the DV boundary takes place long
after the early function of Notch revealed in this work, which is involved in
promoting growth and facilitating wing fate specification. As revealed by the
expression of the Notch target E(spl)m-β, it is not until late
in the second instar that the expression of Notch is restricted to the DV
boundary (see Fig. S1 in the supplementary material). During the process of
wing fate specification that takes place during second instar, it is uniformly
expressed in the whole wing disc (Fig. S1 in the supplementary material).
These results imply that growth also facilitates the reiterative use of
signalling molecules, such as Wg and Notch, to exert different functions
during the development of a multicellular organ like the wing primordium.
At the same time that wing and body wall fate specification takes place in
the wing primordium, Vn is involved in the induction of apterous
expression in the dorsal region (Wang et
al., 2000; Zecca and Struhl,
2002) (see also Fig. S6 in the supplementary material). Consistent
with the model proposed above, the activity of Vn, as monitored by the
expression of apterous, was modulated by tissue growth (see Figs S5,
S6 in the supplementary material). In the absence of Notch activity, even
though Vn expression is not affected (Fig.
2K), Vn appears to reach every wing cell, as apterous
expression was expanded ventrally (see Fig. S5 in the supplementary material).
Increased levels of Wg expression or growth promoted by CycE appear to
re-establish the dorsally restricted range of activity of Vn, as
apterous expansion was blocked under these circumstances (see Fig. S5
in the supplementary material).
Growth promoted by Notch has also been shown to be directly involved in the
specification of the eye within the Drosophila eye-antenna primordium
(Kenyon et al., 2003), a
process that also depends upon the opposing activities of two secreted
signalling molecules, in this case Dpp and Wg. Thus, Notch coordinates in a
very elegant manner both eye and wing primordia tissue growth and eye/wing
specification, by modulating the response of the cells to the activities of
signalling molecules. These results indicate that the same mechanism might be
commonly used in animal development to coordinate tissue growth and fate
specification.
The evolution of wings was crucial in the process of adaptation, allowing
insects to escape predators or colonize new niches. It has recently been shown
that the loss and recovery of wings has occurred during the course of
evolution (Whiting et al.,
2003). This finding would suggest that wing developmental pathways
are conserved in wingless insects and are being re-used. According to our
results, we speculate that adaptative changes in animal size could modulate
the cellular response to signalling molecules such as Wg, thereby helping to
drive some of these extraordinary reversible transitions.
Supplementary material
Supplementary material for this article is available at
http://dev.biologists.org/cgi/content/full/135/24/3995/DC1
ACKNOWLEDGMENTS
We thank N. Azpiazu, S. Cohen, B. Edgar, D. Hipfner, L. Johnston, M. Furriols, J. P. Vincent, the Bloomington Stock Center and the Developmental Studies Hybridoma Bank for flies and reagents, and I. Becam, S. Cohen, H. Herranz and three anonymous reviewers for comments on the manuscript. N.R. was funded by a predoctoral fellowship from the Ministerio de Educación y Ciencia, Spain, and M.M.'s laboratory was funded by Grants from Dirección General de Investigación Científica y Técnica (BFU2004-00167/BMC and BFU2007-64127/BMC) and Generalitat de Catalunya (2005 SGR 00118), intramural funds and the EMBO Young Investigator Programme.
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