University of Washington, Department of Biology, Seattle, WA 98195, USA
* Author for correspondence (e-mail: gerold{at}u.washington.edu)
Accepted 16 September 2005
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SUMMARY |
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Key words: Peripodial epithelium, Compartments, Epithelial morphogenesis, Clonal analysis, Cell lineage, Drosophila
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Introduction |
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Recent studies, however, reveal that PE cells are required for growth and
patterning of the DP during larval development. Cho et al.
(Cho et al., 2000) have shown
that ectopic expression or loss of hedgehog (hh) in the eye
PE results in pattern changes in the DP. Similarly, Gibson and Schubiger
(Gibson and Schubiger, 2000
)
have observed that expression of Fringe in the eye PE leads to smaller eyes
containing minor pattern abnormalities. In addition, Egfr signaling activity
in the PE of the wing disc specifies the notum/hinge of the DP
(Pallavi and Shashidhara,
2003
).
Despite these studies, little is known about the development of PE cells.
The last examination of both PE and DP development was a histological study by
Auerbach (Auerbach, 1936)
describing the morphology of cells in wing and leg discs. Here, we focus on
compartmental organization, proliferation and cell lineage of the PE in wing,
eye and leg imaginal discs. We expand upon Auerbach's study and observe that
epithelial morphogenesis (cuboidal-to-squamous shape change in the PE;
cuboidal-to-columnar shape change in the DP) occurs in only a subset of cells
in the disc epithelia. Furthermore, each disc exhibits a unique temporal and
spatial progression of morphogenesis. We find that squamous morphogenesis
within the PE of wing and leg discs require both hedgehog
(hh) and decapentapelagic (dpp), but not
wingless (wg) signaling. Squamous morphogenesis in the PE of
these discs causes an anterior shift of the anteroposterior (AP) compartment
boundary in the PE relative to the stationary AP boundary in the DP. Finally,
through cell lineage tracing, we find that during larval development cells
born in the PE move into and reside in the DP.
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Materials and methods |
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To monitor cell shape changes in the wing disc, both
hhts2 and wgIL homozygous larvae were
grown at the permissive temperature (18°C) until 65 hours AED (6-7 hours
prior to the cell shape changes in both epithelial layers), then shifted to
the restrictive temperature (29°C) and dissected 12 hours later at early
third instar. For leg discs, the temperature shift and dissection occurred 12
hours later. Both hhts2 and wgIL are
null alleles at the restrictive temperature (Ma, 1993; van den Heuvel, 1993).
We used the same temperature shifts and dissection protocols for larvae of
en-Gal4/UAS dpp; hhts and
en-Gal4/UAS cycD-Cdk4; hhts. Cell morphology was assessed
in progeny of Ubx-Gal4 females crossed to UAS-dad males.
Ubx>dad larvae were raised at 18°C until second instar, when
Ubx-Gal4 becomes limited to the PE
(Pallavi and Shashidhara,
2003), then shifted to 25°C until wandering third instar.
We induced GFP-expressing cell clones in imaginal discs using y w
hs-flp122; act5C>CD2>Gal4 UAS-GFPNLS (III) to
detect dividing cells and determine doubling times of PE and DP cells. To
define compartment identity of clones, we used en-lacZ
[enXho (Hama et al.,
1990)], hh-lacZ [PZ hhp30 (U. Heberlein)] and
ap-lacZ
[aprk560(Diaz-Benjumea and
Cohen, 1993
)].
Mitotic recombination was induced using the FLP/FRT method
(Xu and Rubin, 1993), by a 1
hour heat shock at 37°C at 38 hours, 48 hours and 72 hours AED, and discs
were analyzed at 110 hours AED. Flies of genotype y w
hs-flp122; FRT(42D), Arm-lacZ51A, M(2)60E/P(neoFRT) 42D
P{w+mc=Ubi-GFP (S65T)nls} were used to induce large +/+
(M+) clones in a M/+ background. +/+ clones were
identified by two copies of GFP and the absence of marker Arm-lacZ.
M(2)60E encodes the ribosomal protein L19 (RpL19) with a strong
Minute phenotype (Hart, 1993).
To induce clones in the PE of wing discs, we used the PE-specific
Ubx-Gal4 driver. To study the lineage of PE cells, we treated larvae
of UAS-flp-EBD; act5C>stop>nuclacZ/Ubx-Gal4 with estrogen
during the second (48-72 hours AED) and third (72-96 hours AED) larval instars
(Weigmann and Cohen, 1999).
The PE lineage was also examined by temperature-sensitive regulation of
Ubx-Gal4 activity using a temperature-sensitive version of the
Gal80 protein [tubulin (tub)
promoter-Gal80ts fusion
(McGuire et al., 2003
)]. To
induce PE-specific clones, larvae of tub-Gal80ts; UAS flp;
Ubx-Gal4/act5C>stop>nuclacZ were raised at 18°C until 48-60
hours AED, then heat pulsed for 6 hours at 29°C. Larvae were then placed
back at 18°C until wandering third instar.
Immunocytochemistry
Dissection and fixation of discs has previously been described
(Maves and Schubiger, 1998).
The following primary antibodies were used in overnight incubations at 4°C
in PBNT: rabbit anti-
-Spectrin (1:1000, D. Branton), mouse anti-BrdU
(Becton Dickinson 1:100), rabbit anti-Cyclin A (1:1000, D. Glover), mouse
anti-Engrailed 4D9 (1:20, DSHB), mouse anti-Histone (1:2000, Chemicon), mouse
or rabbit anti-ß-gal (1:1000, Promega and Cappel, respectively), rabbit
anti-p-MAD (1:2000, P. ten Dijke), mouse anti-Ubx (1:100, R. White), rat
anti-Ci 2A (1:2000, Motzny and Holmgren) and rabbit anti-Teashirt (1:3000, S.
Cohen). BrdU (Sigma, 10 µg/ml) incorporation was performed for 30 minutes
before fixation (Johnston and Schubiger,
1996
). Cell death was identified by Acridine Orange staining (1
µg/ml for 5 minutes). Combined confocal images (Bio-Rad MRC 600 system) and
composite images of discs were made using Adobe Photoshop 7.0.
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Results |
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AP compartments in wing and leg disc PE
Imaginal discs are subdivided into AP compartments, the expression of
selector genes cubitus interruptus (ci) and
engrailed (en), maintain A and P compartment identities,
respectively (Blair, 2003).
After mid-second instar, the dorsal selector gene apterous
(ap) further subdivides the DP of wing and haltere discs into dorsal
(D) and ventral (V) compartments
(Garcia-Bellido et al.,
1973
).
We examined the expression of compartment-specific genes (en, ci and ap) and performed clonal analysis to define the compartmental organization in the PE. In wing discs at 55 and 72 hours AED, the boundary of en in the PE is slightly anterior to the boundary of en in the DP (Fig. 3A,B). Between 72-96 hours AED, this boundary shifts to the anterior side of the disc (Fig. 3C). ci-expressing margin cells in the PE abut the en-expression domain and are at the anterior side of the PE by 96 hours AED (Fig. 3I). Thus, all squamous PE cells are in the P compartment and overlie cells of both A and P compartments in the DP (Fig. 3C). As in wing discs, we observed that posterior PE cells in the leg disc undergo a similar anterior shift, but this occurs 12 hours later in development (84 hours AED) (data not shown). We speculate that PE cells located in the P compartment increase their surface area during the conversion to a squamous morphology. This may account for the anterior shift of the AP compartment boundary in the PE of both wing and leg discs.
Clonal restrictions define compartmental boundaries
(Garcia-Bellido et al., 1973).
To test whether clones in the PE, as in the DP, are restricted by
compartments, we induced random GFP-marked clones during the first instar and
analyzed wing and leg discs at 110 hours AED. In 115 wing discs examined, 22
large PE cell clones were found to straddle the en-expression domain
in the PE (Fig. 3D-F). We found
a similar clonal restriction within the en-expression domain in the
leg PE (n=14 large clones in 68 discs). Furthermore, we observed this
clonal restriction even when large PE cell clones were generated using the
Minute system (Morata and Ripoll,
1975
) (Fig. 3G-I,
leg disc; data not shown).
Beginning mid-second instar, ap-lacZ is expressed in the dorsal
compartment of the wing DP (Blair,
1993; Diaz-Benjumea and Cohen,
1993
). ap-lacZ is not expressed in the PE, except for a
small region of posterior margin cells (40+ cells) that border the wing blade
primordia and notum of the DP (Fig.
3L,L', red asterisks). Although ap-lacZ-expressing
PE cells do not co-express Ubx (data not shown), we argue that these
cells are part of the PE based on their apposition to the DP. We induced
random GFP-expressing clones at mid-second instar in the background of
ap-lacZ. These clones were found within either the ap-lacZ
domains of the PE and DP or within the non-ap-lacZ domain of the PE
(n=21 discs, Fig.
3J-L,J'-L'). Therefore, the PE is nearly ventral in
compartment identity except for a small dorsal compartment positioned at the
far posterior side of the PE.
DV lineage restriction in the eye PE and the Bolwig's nerve
In eye discs, clones induced after 48 hours AED define a restriction that
divides the eye into dorsal and ventral compartments
(Baker, 1978;
Campos-Ortega et al., 1978
).
This disc is further subdivided into a large A and small P compartment during
the third instar. Anterior cells differentiate into most of the head capsule,
the eye and parts of the antenna, while posterior cells form the remainder of
antenna and head (Morata and Lawrence,
1978
).
En expression in the eye disc, unlike wing and leg discs, is ubiquitous
throughout the DP with higher levels of expression in the posterior region of
the antenna (Strutt and Mlodzik,
1996). In the PE, En is observed in a small cluster of cells over
the dorsoanterior region of the eye DP, in about half of the discs analyzed
(17/34 discs, data not shown). Given the inconsistent and possible transient
expression of En in the eye PE, we question its control in posterior identity.
However, En is consistently observed in the posterior region of the antennal
PE, and random GFP-expressing clones induced at 72 hours AED in the background
of en-lacZ, were restricted by the en-expression domain
(n=20 clones, data not shown).
To determine whether a DV compartment boundary is present in the eye PE, we
first generated clones during the first larval instar with analysis at 120
hours AED. Interestingly, we observed preferential growth of clones in long,
two- or three-cell wide strips that frequently aligned with the Bolwig's nerve
and extended over both the eye and antennal domains of the disc (data not
shown). Using the Minute system, we found that large +/+ PE cell
clones were restricted into D or V compartments. The boundaries of these
clones co-localized with the Bolwig's nerve
(Fig. 3M-O). The Bolwig's nerve
is the larval optic nerve (Schmucker et
al., 1997), that inserts into the PE (F. Cesares and J. Bessa,
unpublished), where it acts as a physical barrier separating PE cells into D
and V compartments.
|
As wing and leg discs from hhts2/hhts2
larvae are small in size, squamous cells might not form because of fewer
divisions in the discs. To stimulate proliferation in hh-depleted
larvae, we overexpressed cyclin-D-Cdk4
(Datar et al., 2000) in
posterior cells, which includes all squamous PE cells, using the
engrailed-Gal4 (en-Gal4) driver. Experimental
larvae shifted to the hh-restrictive temperature develop larger discs
than those from hhts2/hhts2 larvae
(compare Fig. 4D with 4E) yet
no squamous cells were observed (Fig.
4E'), indicating that Hh signaling is necessary for the
formation of squamous PE cells in wing and leg discs.
Dpp is required for squamous morphogenesis in the PE of wing and leg discs
Because shape changes in the PE of wing and leg discs requires hh
signaling and that dpp expression is hh dependent, we tested
whether dpp function can rescue squamous morphogenesis in
hh-depleted animals. For this we use hhts2
larvae, while also overexpressing dpp (UAS dpp) in the
posterior compartment using the en-Gal4 driver. We found that
activation of dpp in posterior PE cells rescues the
hhts2 phenotype as squamous cells are observed in both
wing and leg discs (Fig.
4F,F'; data not shown for leg disc). This indicates that
hh-dependent dpp activity is sufficient for squamous
morphogenesis in wing and leg discs. To determine whether dpp
signaling is necessary for squamous morphogenesis, we inhibited PE-specific
dpp signal transduction by overexpression of UAS-dad
(Tsuneizumi et al., 1997)
using the wing disc PE-specific driver Ubx-Gal4.
Ubx>dad wing discs are slightly smaller than control
discs. Additionally, these discs display aberrant folding patterns in the DP,
and, more importantly, a PE made of only cuboidal-shaped cells, often stacked
into two or more rows giving the PE a stratified appearance
(Fig. 4G',H',I).
Four out of 20 wing discs from Ubx>dad larvae displayed a small
region of squamous PE cells consistently apposed to clefted folds in the DP
(Fig. 4H,H').
Interestingly, Ubx>dad wing discs that lack squamous PE cells
display only a minor shift of En-expressing PE cells towards the
anterior side of the disc (Fig.
4I-K). Therefore, we conclude that hh-dependent
dpp signal transduction is necessary and sufficient for squamous
morphogenesis of the PE and also the anterior shift of the AP compartment
boundary in wing and leg discs.
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Interestingly, the PE and DP in the wing disc show different distributions
of Dpp activation. In the P compartment of the DP, highest p-MAD expression is
reported in cells adjacent to the AP compartment boundary, whereas in the A
compartment there is broad activation of Dpp signaling
(Tanimoto et al., 2000). By
contrast, we observed p-MAD expression limited to squamous PE cells within the
P compartment (Fig.
5C,C'). Hh expression (hh-lacZ), however, is
identical in the two cell layers, with expression observed in all P
compartment cells (Fig.
5E).
Differences in cell number between the PE and DP
In different imaginal discs, the number of cells that compose the PE and DP
differs dramatically by the end of the third larval instar; our analyses,
however, indicate that this is not always the case during larval development.
We counted the number of cells within the wing PE and DP at 72 hours AED and
110 hours AED. At 72 hours AED, as squamous cells first appear, we counted
291±34 cells in the PE and 996±71 cells in the DP (n=5
discs). These counts are consistent with Steiner's
(Steiner, 1978) from
dissociated early third instar wing discs (1024±32 cells). At 110 hours
AED, we found 2099±236 cells in the PE and estimated 39,200±1170
cells in the DP (n=10 discs). Thus, DP cells outnumber PE cells by
3:1 at 72 hours AED and 20:1 by the end of larval development. Several
hypotheses were tested to account for the increasing discrepancy in cell
number between the disc epithelia, including cell death (Acridine Orange) and
endomitosis; however, both were excluded because during the third instar less
apoptosis was observed in the PE than DP and PE cells remain diploid based on
our DNA measurements (data not shown). We induced random GFP-expressing cell
clones (act5C>Gal4,UAS GFP) at specific times in larval
development (Fig. 6A), to
examine whether different rates of cell division contribute to the discrepancy
in cell numbers between the disc epithelia. To calculate cell doubling times
of both squamous PE and columnar DP cells, we determined the median number of
cells per clone after a defined period of growth
(Neufeld et al., 1998
).
Consistent with previous reports
(Garcia-Bellido and Merriam,
1971; Madhaven and
Schneiderman, 1977
), we found that DP cells in the wing disc
double every 6.3-8.0 hours during the second instar and 10-14 hours during the
third instar (Fig. 6B). Cell
division rates between the disc epithelia differ only when clones were induced
after shape changes in the PE (72-90 hours AED)
(Fig. 6B). At this time,
squamous PE cells divide much slower, every 17-20 hours
(Fig. 6B). Similar observations
were made in leg discs (Fig.
6C). Thus, in wing and leg discs, the appearance of squamous cells
correlates with slower cell division.
For the eye-antennal disc, we compared doubling times of DP cells positioned anterior to the morphogenetic furrow with PE cells positioned over the presumptive eye domain. As in wing discs, eye PE and DP cells exhibit similar doubling times during the second larval instar (Fig. 6D). Unlike wing and leg discs, the doubling times of eye PE cells increase much later in the third instar (Fig. 6D).
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Displacement of PE cells into the DP and changes of Ubx expression
A significant number of act5C>Gal4,UAS GFP clones generated in
wing discs at 48 and 60 hours AED and analyzed at 110 hours AED, contained
cells in both epithelial layers [35.4% (n=143 clones) and 27%
(n=155 clones)]. Similar results were observed in the leg disc [31.1%
(n=103 clones) and 23.9% (n=142 clones)]. The area of these
clones largely resided in the PE with a smaller area in the margin of the DP
(data not shown). Clones that have cells in both disc epithelia were not
fusions of two independent clones because they did not contain twice as many
cells as clones limited to a single epithelium (data not shown). Thus, we
propose that these clones reflect a displacement of cells from one epithelial
layer into the other. If cells from the PE move to DP, this would explain the
increasing number of cells in the DP during the third instar.
To test directly whether cells born in the PE end up in the DP, we
specifically induced clones in the PE using two independent methods: (1)
Ubx-Gal4 activation by a Flp recombinase regulated by estrogen
(Weigmann and Cohen, 1999);
(2) temperature-sensitive regulation of Ubx-Gal4 using the
tubulin-Gal80ts fusion protein
(McGuire et al., 2003
). In the
embryo and first instar larvae, Ubx-Gal4 expression is found in all
cells of the wing disc (Pallavi and
Shashidhara, 2003
), but becomes limited to the PE by the second
instar (Baena-Lopez et al.,
2003
; Pallavi and Shashidhara,
2003
). To induce clones only in the wing PE, we activated Flpase
by feeding larvae estrogen during the second (48-72 hours AED) or third instar
(72-96 hours AED). We expected that the induction of PE-specific clones would
be limited to the PE, and indeed clones of squamous PE cells (sPE) and clones
of margin cells from the PE (mPE) were recovered
(Fig. 7C, 48-72 hours AED).
However, we additionally observed clones in the margin cells of the DP (mDP)
and clones encompassing both disc epithelia, containing squamous PE cells and
margin cells of both disc layers (sPE+mPE+mDP)
(Fig. 7A-C). To rule out the
possibility that perduring Ubx-Gal4 activity labels margin DP cells (mDP), we
performed a lineage analysis of PE cells by temperature-sensitive regulation
of Ubx-Gal4 activity using the tubulin-Gal80ts fusion protein
(McGuire et al., 2003
). Again,
a significant number of clones containing squamous PE cells with margin cells
from both disc epithelia (sPE+mPE+mDP) were observed (data not shown). Both
methods indicate that margin cells of the DP share a lineage relationship with
cells in the PE. To address whether there is a continuous displacement of
cells from the PE into the DP, we fed larvae estrogen during the third instar
(72-96 hours AED). Even at this later induction time, clones spanning both
disc epithelia (sPE+mPE+mDP) and margin cell clones in the DP (mDP) were
observed, yet less frequently (Fig.
7C). This supports the idea that cells born in the PE divide and
produce progeny that are displaced into the DP. We propose that this cell
movement further increases the number of DP cells late in larval life.
Furthermore, while tracing the lineage of PE cells we were able to study the
gene expression of these cells as they are displaced into the DP. In clones
encompassing both disc epithelia, we find Ubx expression in all squamous
cells, rarely in margin cells of the PE and never in cells of the DP (see Fig.
S1 in the supplementary material), indicating that Ubx expression is
turned off when PE cells migrate into the DP.
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Discussion |
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As both hh and dpp are expressed in wing and leg discs
prior to the onset of squamous morphogenesis in the PE, it is clear that their
ability to instruct these shape changes must be regulated by additional
temporal signals. An obvious candidate for such a temporal signal is ecdysone,
which initiates the onset of the larval molts and adult differentiation
(Riddiford, 1993). The
ecdysone signal is mediated by a heterodimer complex consisting of the
ecdysone receptor (EcR) and RXR-homolog Ultraspriacle (Usp)
(Koelle et al., 1991
;
Thomas et al., 1993
;
Yao et al., 1993
). To test
whether squamous morphogenesis is triggered by ecdysone signaling, we induced
usp/ clones and found that cells of such
clones still exhibited normal cuboidal-to-squamous shape changes (data not
shown). Therefore, the temporal cue(s) that initiate disc morphogenesis is
independent of ecdysone signaling and remains unknown.
Previous studies document that shape change of epithelial cells can
activate certain signaling pathways (Wang
et al., 1993; Zhu and Assoian,
1995
). Thus, squamous morphogenesis of the PE may enhance planar
and/or vertical epithelial signaling to promote growth and patterning of the
disc. We made two observations that support this statement. First, where PE
cells fail to undergo squamous morphogenesis, both the disc and adult wing
show an obvious reduction in size (Gibson
et al., 2002
). Second, in discs that lack PE-specific DPP
signaling, folded clefts in the presumptive wing blade primordia are
consistently apposed to a region of squamous PE cells, suggesting
communication between the disc epithelia where shape changes do occur.
Alternatively, the aberrant apposition of AP compartment boundaries in the PE
and DP, owing to a failure in squamous morphogenesis, may result in epithelial
abnormalities such as folded clefts in the DP. Resolving the mechanisms by
which cell shape can affect disc growth and pattern will integrate both
morphogenetic and signaling processes that are crucial for disc
development.
Cells in the DP are included in the peripodial lineage
Pallavi and Shashidhara (Pallavi and
Shashidhara, 2003) performed a lineage analysis of cells in the
wing disc using Ubx-Gal4, UAS flp and
act5C>stop>nuclacZ. As Ubx-Gal4 is initially expressed
in both disc epithelia prior to the second larval instar
(Baena-Lopez et al., 2003
;
Pallavi and Shashidhara,
2003
), cells of both the PE and DP were marked. Their analysis
concluded that cells of the PE and DP share a common origin in the disc
primordium but later become separate lineages, although cells that make up the
PE and DP lineages were never specified. Our results, based on lineage-tracing
cells born in the PE, are in overall agreement with their conclusions;
however, there are some differences. Although Pallavi and Shashidhara
(Pallavi and Shashidhara,
2003
) identified cell clones spanning both disc epithelia, they
could not determine when or where these clones were born. Furthermore, clones
that encompassed cells from both PE and DP were interpreted as either fusions
between two independent clones or as clones that originated early in the
embryo before separation of the two lineages (PE and DP).
Using four different methods, we found that cells that originate within the PE produce progeny that are a part of the DP. We used both the MARCM and estrogen-inducible systems to perform a clonal analysis specific to cells within the PE. These two methods indicate that cells born within the PE produce daughter cells that contribute to the DP. Additionally, a twinspot clonal analysis leads to a similar conclusion and has the advantage of marking cells more directly than either the MARCM- or estrogen-inducible systems. Thus, our analysis indicates a lineage relationship between margin cells in both the PE and DP, and squamous cells in the wing disc, and provides evidence that together these cells comprise the peripodial lineage (Fig. 7).
As cells are displaced from the PE and into the DP they lose Ubx
expression. The loss of Ubx may cause cells to acquire a more distal fate,
forging a possible link between displacement and cell fate changes. Similar
dynamic cell movements, along with changes in gene expression, were observed
in the chick during somite segmentation
(Kulesa and Fraser, 2002). In
addition, cell movements and changes in gene expression, similar to what we
describe here, were reported by Weigmann and Cohen
(Weigmann and Cohen, 1999
),
who observed that leg disc cells born in the most proximal regions of the disc
contribute to more distal leg segments. Finally, we propose that once PE cells
are displaced into the DP they may change their cell fate by altered cell
signaling. Displaced cuboidal cells at the margins of the disc receive not
only planar signals from both epithelial layers, which they are a part of at
different stages in larval development, but also vertical signals from
overlying PE cells after displacement into the DP. These new planar and/or
vertical signals may lead to Ubx repression. We suggest that the
mechanisms that play a role in the development of the imaginal discs may be
functionally similar to mechanisms that regulate primary neurogenesis in
vertebrates. Neural plate formation and patterning cues arise from two
sources: a horizontal source within the plane of an epithelium and a vertical
source that arises from the underlying mesodermal cells
(Weinstein and Hemmati-Brivanlou,
1999
; Wilson and Edlund,
2001
). Our study suggests that patterning of the imaginal discs is
a much more dynamic process with cells exposed to not only signals within the
plane of an epithelium but also vertical signals between disc epithelia.
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ACKNOWLEDGMENTS |
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Footnotes |
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Supplementary material for this article is available at http://dev.biologists.org/cgi/content/full/132/22/5033/DC1
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