1 Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
2 Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115,
USA
3 University of Chicago, 5801 South Ellis Avenue, Chicago, IL 60637, USA
4 The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA
* Authors for correspondence (e-mail: schobem{at}rockefeller.edu and perrimon{at}receptor.med.harvard.edu)
Accepted 19 May 2005
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SUMMARY |
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Key words: Cell migration, Oogenesis, Drosophila, ETS, Notch, JAK/STAT, RTK, Border cells
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Introduction |
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The migration of border cells (BCs) in the Drosophila egg chamber
provides a unique system with which to genetically dissect the mechanisms
regulating invasive cell migration in vivo
(Montell, 2003;
Rorth, 2002
). During
oogenesis, a group of approximately eight cells, called BCs, is specified at
the anterior pole of the ovarian follicular epithelium
(Montell et al., 1992
). At
stage 9 of oogenesis, BCs change their shape, exit the epithelium and become
migratory (Fig. 1A). BCs
comprise two inner cells, called polar cells, surrounded by six to eight outer
BCs (Niewiadomska et al.,
1999
). The highly dynamic and polarized cytoskeleton of outer BCs
enables them to migrate (Fulga and Rorth,
2002
) and transport the non-motile polar cells with them. BCs
migrate in between nurse cells (NCs) until they reach the NC-oocyte boundary
at stage 10 of oogenesis.
A variety of molecules have been identified to regulate BC migration. The
Drosophila C/EBP transcription factor homolog Slow border cells
(Slbo) is a key regulator of BC migration
(Montell et al., 1992). Slbo
is specifically expressed in BCs at the time when BCs become migratory. Slbo
promotes the expression of shotgun (shg), the gene encoding
the Drosophila homolog of the cell-cell adhesion molecule E-Cadherin
(DE-Cad), which has been shown to be crucial in both BCs and NCs for BC
motility (Niewiadomska et al.,
1999
). Specifically, loss of shg leads to delayed BC
migration, and it has been speculated, although not tested, that an increase
in DE-Cad expression might also result in BC migration defects. These findings
have led to a model proposing that DE-Cad-containing adhesive complexes,
together with myosins, provide the traction between BC and NC surfaces that
allows BCs to migrate (Fulga and Rorth,
2002
; Geisbrecht and Montell,
2002
).
Genetic screens have further identified four signaling pathways that
control the stereotypic migration of BCs. During early oogenesis, the
cytokine-like molecule Unpaired (Upd) is secreted from the pair of anterior
polar cells to activate the JAK/STAT pathway in the surrounding cells.
JAK/STAT activation induces the expression of slbo, which specifies
BCs (Silver and Montell,
2001). Like JAK/STAT, Notch signaling is also required for the
expression of slbo in anterior follicle cells
(Gonzalez-Reyes and St Johnston,
1998
), indicating that Notch signaling might be crucial for BC
specification and migration. Once specified, BCs exit the follicular
epithelium and become migratory, a process that relies on nuclear hormone
signaling (Bai et al., 2000
).
Ecdysone hormone co-receptor taiman (tai) mutants have
defects in BC migration even though Slbo is expressed and DE-Cad-containing
adhesive complexes are formed at the BC-NC interface, leading to the proposal
that the migration defects of tai mutant BCs are due to problems in
the turnover of adhesive complexes (Bai et
al., 2000
).
Two RTK pathways, the Platelet-Derived Growth Factor/Vascular Endothelial
Growth Factor Receptor (PVR) and the Epithelial Growth Factor Receptor (EGFR)
pathways, control the migration of BCs. Pvf1, one of three secreted PVR
ligands (Duchek et al., 2001),
is expressed in an increasing gradient along the anteroposterior (AP) axis of
the egg chamber. This gradual expression, together with the delayed or
misrouted migration that results when dominant-negative forms of both EGFR and
PVR are co-expressed in BCs, or when the ligand Pvf1 is ectopically expressed
in ovarian egg chambers, have led to a model whereby PVR and EGFR exert
redundant functions in guiding BC migration
(Duchek and Rorth, 2001
;
Duchek et al., 2001
;
McDonald et al., 2003
).
Although the MAPK pathway is activated in migrating BCs
(Duchek and Rorth, 2001
), it is
not known whether its target genes are crucial for BC migration.
The ETS (E-26) transcription factor gene yan, which encodes the
Drosophila homolog of the TEL oncogene
(Laudet et al., 1999), is one
of the main target genes of the Notch and MAPK signal transduction pathways
during photoreceptor specification in the Drosophila developing eye
(O'Neill et al., 1994
;
Rohrbaugh et al., 2002
). While
Notch-mediated Suppressor of Hairless [Su(H)] activity promotes yan
expression (Rohrbaugh et al.,
2002
), MAPK pathway stimulation above a critical threshold
triggers Yan phosphorylation (Rebay,
2002
; Rebay and Rubin,
1995
). This post-translational modification of Yan stimulates its
nuclear export and subsequent degradation, enabling photoreceptor cells to
differentiate. Thus, Yan, which is antagonistically regulated by Notch and RTK
signaling, probably provides a negative-feedback loop that allows the tight
regulation of RTK-mediated cell differentiation.
Although many molecules involved in BC migration have been accounted for, it is not yet clear how input from multiple signaling pathways is integrated to ensure the fidelity and precise orchestration of cell movements. Here, we describe a novel function for Yan in BC migration. We find that Yan is dynamically expressed and regulated in migrating BCs. Specifically, we find that upregulation of Yan expression in the follicular epithelium depends on the Notch and JAK/STAT signaling pathways, and precedes BC motility and exit from the follicular epithelium, whereas downregulation of Yan in response to PVR and EGFR is important for continued invasive migratory behavior. We further demonstrate that BC migration can be delayed by increasing DE-Cad levels and that Yan may influence this process by regulating the turnover of DE-Cad-containing adhesive complexes at the plasma membrane.
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Materials and methods |
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Immunohistochemistry and immunofluorescence
Ovarioles were dissected from 5-day-old, well-fed females in Schneider S2
medium. For ß-galactosidase staining, ovaries were dissected, fixed for
10 minutes in 0.1% glutaraldehyde in PBS-0.1% Triton X-100 and stained as
described previously (Bai et al.,
2000). For immunofluorescence analysis, ovaries were fixed with 4%
formaldehyde in PBS-0.1%Triton X-100 for 30 minutes. Ovaries were incubated in
primary antibody overnight, washed twice for 20 minutes in PBS-0.1% Triton
X-100, followed by a 2-hour incubation in secondary antibody containing
Alexa-568-Phalloidin (1:100, Molecular Probes) to stain the actin
cytoskeleton. After washing the tissue twice for 30 minutes with PBS-0.1%
Triton X-100, it was mounted in Slow Fade (Molecular Probes). The following
primary antibodies were used: mouse anti-FAS III at 1:10 (2B5, Developmental
Hybridoma Bank); mouse anti-Yan at 1:200 (I. Rebay); rat anti-Slbo at 1:3000
(P. Rorth); rat anti-DE-Cad at 1:100 (H. Oda); and rabbit anti-ß-Gal at
1:2000 (Cappel). As secondary antibodies, Alexa-488 and Alexa-598 were used at
1:500 (Molecular Probes). Images were obtained using a Leica-SP2 confocal
microscope.
FM1-43 uptake experiment
Double-stranded RNA was generated against the following regions using the
Ambion MegaScript kit: Yan (NM_078731) nucleotides 394-1359 and GFP
nucleotides 3-549 of the open reading frame. SL2 cells were seeded in
serum-free Schneider's medium (Gibco) into a 96-well plate, with
8x105 cells and 1 µg dsRNA per well). Serum was added
after 1 hour of serum starvation and cells were grown for 4 days at 25°C.
SL2 cells (8x105) were transfected with 0.1 µg
MT(metallothionin)-YanACT using effectene transfection
reagents. Expression was induced with 1 mM CuSO4 12 hours before
the endocytosis assay. Cells were replated on eight-well coverslip chambers
coated with concavidin A and washed with HL3 medium
(Kuromi and Kidokoro, 1999).
HL3 medium was exchanged with HL3 medium containing 10 µM FM1-43 (Molecular
Probes). FM1-43 incorporation was observed in real time. Eight confocal
sections per minute were acquired on a Leica-SP2 inverted confocal microscope
over a time period of 30 minutes. A maximum projection was generated for each
frame and the relative fluorescence intensity was plotted against time to
assess the kinetics of FM1-43 incorporation. Addition of CuSO4 in
mock-transfected cells did not alter the endocytic rate when compared with
untreated control cells.
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Results |
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Yan modulates DE-Cad-containing adhesive complexes
To address whether the yan mutant phenotype is caused by a
misspecification of BCs, we examined Slbo expression in
yan443 mutant BCs. Removal of Yan function had no effect
on Slbo expression (Fig.
3A,A'). In addition, expression of the polar cell-specific
marker Fasciclin 3 (Fas3) was unaffected, indicating that the fate of
migratory outer BCs was not transformed into non-migratory polar cells
(Fig. 3B,B'). Together,
these data suggested that Yan does not function to specify BCs or to
discriminate between inner versus outer BC identity.
To test whether Yan regulates cell motility, we analyzed DE-Cad expression
in yan mutant BCs. DE-Cad is a key regulator of BC migration
(Niewiadomska et al., 1999)
and the dynamic regulation of E-cadherin is crucial for
epithelial-to-mesenchymal transitions and morphogenetic cell movements in many
systems (Thiery, 2002
). In
wild-type BC clusters, DE-Cad localized primarily to the surface between polar
cells and outer BCs, as well as to the interface between outer BCs
(Fig. 3C). It is further
detectable at a significantly lower level at the margins between BCs and NCs.
In yan443 mutant BC clusters, DE-Cad was strongly
expressed in both polar cells and mutant outer BCs
(Fig. 3C'). Specifically,
DE-Cad was strongly enriched at the boundary between BCs and squamous follicle
cells (arrow, Fig. 3C',
see also Fig. S2 in the supplementary material). Interestingly, even partially
yan443 mutant BC clusters can show severe migration
defects, and yan mutant BCs stay connected to squamous follicle
cells, showing elevated DE-Cad accumulation at their plasma membrane interface
(arrows, Fig. 3D,D').
|
The transcriptional suppression of E-Cadherin is a crucial step in
mediating epithelial-mesenchymal transitions
(Thiery, 2002). We therefore
tested whether Yan might function to suppress shg transcription to
allow BCs to exit the follicular layer and become migratory. However,
shg transcription was not affected in yan mutant BCs, nor
could we find significant alterations in the activity of a
shg-luciferase reporter construct in S2R+ cells, either when
yan expression was knocked down by RNA interference using a
yan-specific double-stranded RNA (yanRNAi) or
when YanACT was overexpressed (data not shown), indicating that Yan
does not affect shg transcription.
|
yan functionally interacts with slbo
Slbo is specifically expressed in BCs and is a crucial regulator of
shg expression and BC migration. Similar to Slbo, Yan is upregulated
in BCs just before they become migratory
(Fig. 1). To test whether the
expression and upregulation of Yan requires Slbo function, we analyzed Yan
expression in slbo1310 mutant egg chambers. Interestingly,
Yan was strongly expressed in BCs of stage 9 egg chambers
(Fig. 6A), indicating that Yan
expression does not require Slbo activity. We further noticed that Yan
remained strongly expressed in slbo1310 BCs that failed to
migrate (Fig. 6B), suggesting
that migration towards the NC-oocyte boundary is required for Yan
downregulation in BCs.
Our data indicate that the two transcription factors Yan and Slbo do not regulate the expression of one other (Fig. 3A', Fig. 6A), suggesting that they might not operate in a direct, linear pathway. However, Yan and Slbo could instead function in independent pathways that converge to regulate BC migration. We therefore tested whether yan and slbo functionally interact in BCs. While overexpression of YanWT had no or little effect on BC migration, expression of constitutively active YanACT severely delayed their migration (Fig. 6C). Furthermore, overexpression of YanWT in heterozygous slbo1310 mutants weakly enhanced BC migration defects, whereas ectopic expression of YanACT in heterozygous slbo1310 mutant BCs caused BC migration defects that were even stronger than the defects observed in homozygous slbo1310 mutant egg chambers. Strikingly, BC migration was completely blocked in homozygous slbo1310 mutants overexpressing YanWT (Fig. 6C). Altogether, these data indicate that Yan and Slbo functionally interact to control BC migration without influencing the expression of each other.
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|
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In addition to Notch signaling, the JAK/STAT pathway has recently been
shown to control the specification of various follicle cell fates
(Keller Larkin et al., 1999;
Xi et al., 2003
) and BC
migration (Beccari et al.,
2002
; Silver and Montell,
2001
) (Fig. 7A). To
test whether JAK/STAT signaling regulates Yan expression in BCs, we generated
positively marked stat92E mutant clones. stat mutant
follicle cells showed strongly reduced Yan expression (arrows,
Fig. 7I,I') when compared
with the corresponding wild-type follicle cells (arrowheads,
Fig. 7I,I') in stage 8
egg chambers. stat mutant BCs, as well as squamous follicle cells,
did not express Yan (arrows, Fig.
7J,J'), whereras it was normally expressed in wild-type
anterior terminal cells (arrowhead, Fig.
7J,J'). Similar results were obtained in clones that were
mutant for hopscotch, the JAK kinase that activates Stat92E (data not
shown). Interestingly, BCs of hypomorphic
statF/statP1608 mutant egg chambers
showed severe BC migration defects and a significant reduction in Yan
expression (data not shown), suggesting that Yan is a crucial target gene of
the JAK/STAT pathway in BCs and anterior terminal cells.
|
Yan is downregulated in response to increasing PVR and EGFR signaling
Yan expression decreases in wild-type BCs as they migrate from the anterior
pole of stage 9 egg chamber towards the NC-oocyte boundary
(Fig. 1), but remains strongly
expressed in slbo mutant BCs, which fail to migrate and remain at the
anterior tip of stage 10 egg chambers (Fig.
6). Furthermore, overexpression of yanWT had
little or no effects on BC migration, whereas expression of activated
yan (yanACT), a form of Yan that cannot be
post-translationally regulated by phosphorylation via the MAPK pathway
(Rebay and Rubin, 1995),
showed a severe delay in BC migration. These data, together with the recent
finding that Pvf1 is expressed in an increasing gradient along the AP axis
towards the NC-oocyte boundary, and that the PVR and EGFR signaling pathways
are active in BCs and are crucial for their migration
(Duchek and Rorth, 2001
;
Duchek et al., 2001
;
McDonald et al., 2003
),
suggested that the gradient of PVR and EGFR activity might control the
spatiotemporal expression of Yan during the course of BC migration
(Fig. 8A).
To test whether the PVR and EGFR pathways can trigger Yan downregulation in BCs, we expressed activated forms of PVR, EGFR and the RTK signal transducer RAF in BCs, and assayed Slbo and Yan expression. Whereas Slbo was expressed at normal levels in BCs that expressed activated forms of PVR, EGFR or RAF (Fig. 8B-E), Yan protein levels were strongly reduced (Fig. 8B'-E'). As an internal control, normal Yan expression levels were observed in squamous follicle cells where slbo-Gal4 is not expressed. Furthermore, expression of activated FGFR hardly affected BC migration and Yan expression levels were comparable to wild type (data not shown).
|
Our data support a model where JAK/STAT and Notch signaling specify anterior terminal cells including BCs, resulting in a strong expression of Yan in BCs; increasing RTK activity can decrease Yan expression as BCs approach their destination (Fig. 9).
The Notch and RTK signaling pathways function to control AP axis specification at early stages of oogenesis, resulting in expression of the ETS transcription factor pointed (pnt) at the posterior pole. In photoreceptor cells, RTK activation induces the downregulation of Yan, which subsequently allows pnt expression and a switch in cell fate. Thus, we tested whether Yan expression at the initiation of BC migration might suppress pnt expression, and Yan downregulation at the NC-oocyte boundary might lead to pnt expression, and therefore, potentially, induce BC differentiation. RNA in situ hybridization data and analysis of pntP(lacZ) expression in ovaries revealed that pnt is not expressed in BCs at any stage of oogenesis, and ectopic expression of slbo-Gal4::UAS-pntP2 does not alter BC motility (data not shown). Furthermore, ectopic activation of PVR in BCs downregulated Yan expression (Fig. 8C') and delayed BC migration without induction of pntP(lacZ) in BCs (Fig. 8I). We thus conclude that although the Notch and RTK signaling pathways modulate Yan expression levels in both photoreceptor cells and BCs, the mechanisms used are not identical, and the transcriptional responses and downstream mechanisms depend, at least in part, on the developmental context.
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Discussion |
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Yan is dynamically expressed in migrating border cells
Our study reveals that during oogenesis yan mutant BCs are
defective in their invasive migratory behavior. In addition, we found that Yan
is upregulated as BCs exit the epithelium to become migratory, and that
subsequently Yan protein levels decay as BCs approach the NC-oocyte boundary
(Fig. 1). Because Yan has
previously been shown to function as a transcriptional repressor and an
inhibitor of neuronal differentiation, we tested whether it regulates BC
identity. Although we cannot completely exclude this possibility, BC markers
are properly expressed in the absence of Yan. Thus, we propose that Yan
promotes BC motility, an hypothesis which is supported by the observations
that: (1) Yan is upregulated prior to the BCs exiting the follicular
epithelium to become migratory; (2) Yan protein levels decrease progressively
as BCs approach their final destination; and (3) yan mutant BCs
exhibit a delay in migration. Interestingly, ectopic expression of
constitutively activated Yan in BCs also delays their migration, suggesting
that the spatiotemporal activity of Yan protein needs to be precisely
controlled during the migratory process.
Yan coordinates signal inputs from different pathways
The dynamic expression of Yan is crucial for BC migration, as indicated by
the migratory defects associated with both gain- and loss-of-function alleles
of yan. Analysis of mutations in the JAK/STAT
(Silver and Montell, 2001;
Xi et al., 2003
) and Notch
(Gonzalez-Reyes and St Johnston,
1998
) signaling pathways revealed that they are required for the
expression of at least two transcription factors that are crucial for BC
migration and which themselves influence DE-Cad activity. Slbo is specifically
expressed in BCs and enhances shg transcription. Yan, by contrast, is
expressed in anterior terminal cells, but becomes upregulated in BCs at the
time they exit from the epithelium to become migratory. Yan might enhance
DE-Cad turnover to facilitate the transition from an immobile epithelial state
to a migratory one. Enhanced BC migration defects of hypomorphic slbo
mutant egg chambers overexpressing Yan further underscore their interaction to
regulate DE-Cad expression and BC migration.
Interestingly, we find that Yan expression levels gradually decrease as BCs
move along an increasing PVR/EGFR activity gradient
(Duchek and Rorth, 2001;
Duchek et al., 2001
;
McDonald et al., 2003
). Yan
has been shown to be phosphorylated by the EGFR-MAPK pathway, which triggers
its nuclear export and protein degradation
(Rebay and Rubin, 1995
).
Consistent with these previous studies, expression of dominant-active PVR and
EGFR in BCs blocks BC migration and abrogates Yan protein expression, whereas
yan transcript or enhancer trap expression is still detectable.
Expression of activated Ras and Raf similarly induced Yan downregulation,
consistent with an involvement of the canonical Ras/MAPK pathway in mediating
PVR/EGFR signaling. We note, however, that although BC migration was
significantly delayed upon ectopic expression of activated Ras, activated Raf
hardly affected their ability to migrate. The basis of this difference, which
might be due to complex feedback loops between the implicated signaling
pathways, is unclear at the present time and will need to be investigated
further.
Yan regulates the accumulation of DE-Cad containing adhesive complexes
Is the function of Yan to facilitate the transition of BCs from an
epithelial to a migratory state, or to promote their motility? Although
E-Cadherin is often downregulated as cells transit from an epithelial to a
mesenchymal-like migratory state (Thiery,
2002), this may not be the case in BCs, as DE-Cad is strongly
expressed in BCs and shg mutant BCs fail to migrate
(Niewiadomska et al., 1999
).
However, BCs mutant for yan or tai accumulate ectopic
DE-Cad-containing adhesive complexes (Bai
et al., 2000
). Consistent with these observations, ectopic
stimulation of PVR in BCs, which enhances tai mutant BC migration
defects, also results in elevated, cortical DE-Cad staining
(McDonald et al., 2003
). Even
though the observed BC migration defects in these mutants might not be due to
altered surface levels of DE-Cad only, we found that overexpression of DE-Cad
alone can cause migration impaired BCs. E-cadherin not only mediates
homophilic cell-cell adhesion but also functions together with its binding
partners as a key regulator of the cortical actin cytoskeleton. It is
therefore interesting to note that follicle cells overexpressing DE-Cad show
severely enhanced filamentous actin staining (data not shown).
Our experiments revealed that DE-Cad was elevated in yan mutant
BCs and suppressed upon expression of UAS-yanACT,
suggesting that Yan controls, at least in part, DE-Cad expression in BCs.
These observations find further support in the partial rescue of
slbo-Gal4::UAS-yanACT-induced BC migration defects upon
co-expression of UAS-DE-Cad. How does Yan affect DE-Cad expression in
BCs? Although the function of Yan as a transcriptional repressor in various
tissues (Rebay, 2002) suggests
that it may act as a transcriptional regulator of shg, we could not
detect a change in shg transcription in yan mutant follicle
cells. However, increased FM1-43 incorporation in Drosophila SL2
cells overexpressing YanACT, and a decrease in incorporation after
yanRNAi, suggests a change in endocytic activity.
E-Cadherin has previously been found in endocytic compartments and endocytosis
has been speculated to modulate E-Cadherin activity regulation during
morphogenetic movements (Lanzetti et al.,
2004
; Paterson et al.,
2003
). Interestingly, blocking endocytosis by the expression of
dominant-negative Rab5 lead to severe BC migration defects and increased
DE-Cad staining. Consistent with our observations, expression of shg
under a heterologous promoter has recently been shown to rescue shg
mutant BC migration defects, suggesting that the dynamic expression of DE-Cad
in BCs might depend on both transcriptional and post-transcriptional
mechanisms (Pacquelet et al.,
2003
). Based on these results, we favor a model whereby Yan might,
at least in part, function to regulate DE-Cad turnover, possibly through the
transcriptional regulation of as-yet-unidentified components of the endocytic
machinery.
ETS factors during epithelial-mesenchymal transition and metastatic cancer
ETS transcription factors are not only regulators of morphogenetic
processes but have also been identified as oncogenes. Indeed, several ETS
factors are upregulated in invasive cancers and are currently used as
molecular markers to grade their invasiveness
(Dittmer and Nordheim, 1998;
Oikawa and Yamada, 2003
;
Sharrocks, 2001
). The
molecular function of ETS factors in tumorigenesis is not clear, as they can
act as both oncogenes and tumor suppressors. Our observations that
yan is associated with similar gain- and loss-of-function phenotypes
support both a positive and negative function on invasive migration, dependent
on activity levels and possibly on available cofactors. Furthermore, the
complexity of invasive tumors makes it difficult to assess what function ETS
factors have, as they are upregulated not only in the cancerous tissue but
also, for example, in forming blood vessels during tumor angiogenesis.
Finally, our finding that Yan levels are regulated by JAK/STAT, Notch and RTK
signaling pathways, which have been implicated in metastatic cancer, is
another strong connection between Yan-like ETS factors and tumorigenesis.
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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/132/15/3493/DC1
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