Institut für Genetik, Heinrich-Heine Universität Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
* Author for correspondence (e-mail: knust{at}uni-duesseldorf.de)
Accepted 21 February 2005
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SUMMARY |
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Key words: Zonula adherens, crumbs, Notch, RhoA (Rho1), Retinal development
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Introduction |
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The Drosophila compound eye is ideally suited for the dissection of the genetic and cell biological requirements that govern pattern formation in a complex system. The adult eye is composed of about 750 individual units, called ommatidia, that are arranged in a highly stereotypic pattern (Fig. 1A). Each ommatidium is composed of eight photoreceptor cells, four cone cells and two primary pigment cells. Ommatidia are separated from each other by secondary and tertiary pigment cells, and the number and arrangement of these defines the precise honeycomb-like arrangement of the ommatidia. Mechanosensory bristles are formed at alternating vertices of the hexagonal array (Fig. 1A,A').
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Programmed cell death during pupal development of the retina depends, as in
other developmental systems, on the activation of the caspase cascade
(reviewed by Hay, 2000;
Song and Steller, 1999
).
However, the upstream events that initiate apoptosis and decide which cells of
the interommatidial lattice survive and which die are poorly understood. The
regulation of cell number by programmed cell death depends on at least two
processes. First, signalling between neighbouring cells is crucial for the
determination of cell fate, including the decision to live or die. Second,
formation of correct adhesive structures between cells is an important aspect
of cell fate specification and pattern formation. Two major signalling
cascades, mediated by the EGF and Notch receptors respectively, control cell
fate specification and apoptosis in the Drosophila retina during
pupal development. The EGF receptor/Ras pathway is required throughout eye
development for the recruitment of cells into the developing ommatidia, which
in turn prevents them from undergoing apoptosis
(Freeman, 1996
).
Overexpression of an activated form of the EGF receptor allows all the cells
in the developing eye to survive (Miller
and Cagan, 1998
). Expression analysis suggests that the signalling
centre, which secretes the ligand Spitz, is localised in the cone cells and/or
primary pigment cells. Ablation of these cells leads to increased programmed
cell death (Miller and Cagan,
1998
). The second signalling pathway involved, the Notch pathway,
antagonises EGF receptor signalling. Activation of Notch-mediated signals
between interommatidial precursor cells is required to remove excess cells.
Thus, loss of Notch function in the IOCs results in the survival of
surplus lattice cells, and this even occurs when the source of the survival
signal has been eliminated by ablation of the primary pigment cells
(Miller and Cagan, 1998
).
Formation of adhesive contacts between neighbouring cells is the second
important prerequisite for pattern formation. Cells within a given tissue can
be sorted by selective adhesion, and the contacts they make may determine
which signals they receive, and hence their future behaviour (reviewed by
McNeill, 2000;
Tepass et al., 2002
). In the
developing pupal retina, the IOCs are initially arranged in double or triple
rows between the forming ommatidia. These cells then rearrange to form a
single row of cells, aligned head-to-tail. Only after this reorganisation is
complete are the surplus cells eliminated, suggesting that this cell-sorting
process is a prerequisite for programmed cell death
(Brachmann and Cagan, 2003
;
Reiter et al., 1996
;
Wolff and Ready, 1991
). The
importance of correct cell sorting during eye development is manifested by the
retinal phenotype of flies that are mutant for irregular chiasm
C-roughest (irreC-rst). Here, sorting of the IOCs into single
rows does not occur, leaving the cells in double and triple rows
(Reiter et al., 1996
). In the
wild-type retina, IrreC-rst accumulates at the interface between primary
pigment cells and IOCs, and loss of IrreC-rst or its ubiquitous expression on
all membranes prevents the end-to-end alignment of cells and the subsequent
removal of supernumerary cells (Reiter et
al., 1996
). So far, only two genes have been reported to affect
the distribution of IrreC-rst, Notch and Delta. Reducing the
function of either during the crucial period causes a redistribution of
IrreC-rst throughout the apical membranes, and prevents sorting and programmed
cell death (Gorski et al.,
2000
).
As mentioned above, the recruitment and reorganisation of cells during eye
development takes place in a single-layered epithelium. In spite of the
morphogenetic changes that occur as development advances, such as the
spreading of the cone cells over the photoreceptor cell cluster early in
pupation or the sheathing of the cone cells by the primary pigment cells, the
basic features of the epithelium - cell-cell adhesion and apicobasal polarity
- are largely maintained. It is therefore tempting to assume that disruption
of either of these processes might interfere with the sorting machinery and
ultimately with programmed cell death. Several genes, such as
shotgun, which encodes the homophilic cell adhesion protein
DE-cadherin (Tepass et al.,
1996; Uemura et al.,
1996
), and armadillo, which codes for the
Drosophila homologue of ß-catenin (Peiffer and Wieschaus, 1990),
are involved in the adhesion process itself. Other genes are known to control
apicobasal polarity and adhesion in embryonic epithelia. One of these,
crumbs (crb), encodes a large transmembrane protein whose
extracellular domain is composed of 30 EGF-like repeats
(Tepass and Knust, 1990
;
Tepass et al., 1990
). The four
C-terminal amino acids - ERLI - of its short cytoplasmic domain serve to
recruit a multiprotein complex that forms apical to the zonula adherens (ZA).
This complex contains the MAGUK (membrane-associated guanylate kinase) protein
Stardust (Sdt) (Bachmann et al.,
2001
; Hong et al.,
2001
), the four-PDZ-domain protein DPATJ [previously known as
Discs lost (Pielage et al.,
2003
)] (Klebes and Knust,
2000
) and the single PDZ-domain protein Lin7
(Bachmann et al., 2004
).
Mutations in crb do not interfere with the formation or maintenance
of the epithelial tissue structure of the eye imaginal disc, and the external
morphology of the adult eye of such a mutant is essentially normal
(Johnson et al., 2002
).
However, loss of crb during eye development prevents the elongation
of the photoreceptor cells, which is manifested in the formation of shorter
and thicker rhabdomeres, and results in shortening of the stalk membrane, i.e.
the part of the apical membrane between the adherens junctions and the
rhabdomere (Izaddoost et al.,
2002
; Johnson et al.,
2002
; Pellikka et al.,
2002
).
We set out to analyse the role of cell adhesion at earlier stages of eye development, particularly at stages when cells are subjected to major rearrangements. We wished to determine to what extent perturbation of their adhesive properties might influence cell sorting. Here, we show that IrreC-rst colocalises with DE-cadherin in the zonula adherens at the border between primary pigment cells and IOCs in pupal eye discs. Elimination of the continuous belt of DE-cadherin in the apical regions of the cells, or its disruption, leads to ectopic localisation of IrreC-rst, which in turn prevents cell sorting and programmed cell death. Our data further suggest that the restriction of IrreC-rst to the membranes between primary pigment cells and IOCs is controlled by Notch signalling.
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Materials and methods |
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All flies were raised on a standard cornmeal agar food at 25°C, if not indicated otherwise in the figure legends. The pupae were staged at either 25°C [100% pupal development (p.d.) corresponds to 103 hours)] or 20°C (100% p.d.=160 hours). Eye discs were dissected at the time points indicated in the text.
Scanning electron microscopy of adult compound eyes
Flies were decapitated using razor blades, and a longitudinal incision was
made between the eyes. Specimens were collected in 30% ethanol and dehydrated
by passage through a graded ethanol series (50%, 70%, 90%, 95%, 100%),
followed by incubation in acetone (100%), tetramethyl-silane (TMS):acetone
(1:1) and 100% TMS. Specimens were gold coated using a SEM UNIT 5100 and
examined with a Leitz-AMR1000 scanning electron microscope.
Immunohistochemistry
Antibody staining of eye discs was performed as described earlier
(Reiter et al., 1996). The
pupae were allowed to develop for various times (usually between 16 and 42%
p.d.) after puparium formation at 20 or 25°C. The retina-brain complex was
dissected in PBT (PBS with 0.1% Triton X-100), fixed for 1 hour in 4%
paraformaldehyde and blocked with normal goat serum. The following primary
antibodies were used: mouse anti-IrreC-rst [mAb 24A5.1, 1:50; obtained from K.
Fischbach (Schneider et al.,
1995
)]; rat anti-DE-cadherin or anti-
-Catenin
[anti-DE-Cad1, anti-Cat2; 1:50 and 1:100, respectively; obtained from T.
Uemura (Oda et al., 1994
;
Uemura et al., 1996
)] and
mouse anti-CD2 (1:500; Biozol). Anti-rabbit-Cy2 and anti-mouse-Cy3 (1:200,
Transduction Laboratories) were used as secondary antibodies. Immunostained
imaginal discs were embedded in glycerol/propylgallate and analysed with a
Leica TCS NT confocal microscope. Images were processed and mounted using
Adobe Photoshop 6.0 and Canvas 9.0.
Detection of cell death
Third-instar larval imaginal discs and pupal eye discs 5-10 hours after the
onset of interommatidial apoptosis, were stained with Acridine Orange
according to Spreiji (Spreiji,
1971). Third-instar larval and pupal (31% p.d.) imaginal discs
were rapidly dissected in cold PBS and stained in 0.5 µg/ml Acridine Orange
for 15 minutes and 0.1 µg/ml Acridine Orange for 5 minutes, respectively.
After a brief wash, the retinal preparations were mounted in PBS and
immediately examined with a Zeiss Axiophot 2.
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Results |
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These findings raised the issue of where precisely Crbintra must
be overexpressed in order to produce the rough-eye phenotype. It has
previously been shown that overexpression of crbintra in
the developing eye leads to ectopic localisation of Armadillo and DPATJ, and
affects the length of the adherens junctions in photoreceptor neurons
(Fan et al., 2003;
Izaddoost et al., 2002
;
Tanentzapf and Tepass, 2003
).
However, we never observed any roughening of the eyes upon overexpression of
crbintra driven by either elav-Gal4 or
Rh-Gal4 (data not shown), which induce expression
exclusively in photoreceptor cells. This suggests that the rough-eye phenotype
results from persistent expression of UAS-crbintra in the
support cells, rather than in photoreceptor cells. To determine in which cells
GMR-Gal4 and sev-Gal4 are expressed, we analysed their
activity during pupal development, using the rat transmembrane protein CD2
(Dunin-Burkowski and Brown,
1995
) as a reporter. GMR-Gal4 was found to be expressed
in all cell types (pigment, cone and photoreceptor cells) during the first
half of pupal development, but later becomes restricted mainly to the
photoreceptor cells. sev-Gal4 is expressed in cone cells and in a
subset of photoreceptor cells (data not shown). The only support cells that
express Gal4 in both lines are the cone cells, suggesting that targeted
expression of UAS-crbintra in these cells is responsible
for the mutant phenotype. The stronger roughening of the eye in
GMR-Gal4>UAS-crbintra flies in comparison with
sev-Gal4>UAS-crbintra could be due to the fact that
expression in the pigment cells in
GMR-Gal4>UAS-crbintra may also contribute to the mutant
phenotype.
Overexpression of crbintra prevents sorting of interommatidial cells
Disruption of any one of several morphogenetic processes can lead to a
rough-eye phenotype; among these are the prevention of cell sorting,
inhibition of programmed cell death during pupal development
(Hay et al., 1994;
Reiter et al., 1996
), and an
increase or reduction in the number of photoreceptor neurons
(Basler et al., 1991
;
Carthew and Rubin, 1990
).
Semi-thin sections of eyes overexpressing crbintra reveal
normal numbers of photoreceptor neurons (data not shown). Therefore we
analysed pupal discs overexpressing crbintra for defects
in cell sorting. To do so, wild-type and
GMR-Gal4>UAS-crbintra pupal eye discs at different
developmental stages were stained with an anti-DE-cadherin antibody to outline
the cell membranes. In wild-type pupae at
16% p.d., when the two primary
pigment cells have been specified, two or more layers of interommatidial
(lattice) cells (IOCs) separate individual ommatidia
(Fig. 2A). Between 18 and 21%
p.d., when the two primary (1°) pigment cells have completely enwrapped
the cone cell quartet, the IOCs reorganise, so that each of them makes contact
with at least two primary pigment cells in adjacent ommatidia. This results in
the formation of a single row of lattice cells, aligned end-to-end, between
individual ommatidia (Fig. 2B).
The surplus cells are eliminated by programmed cell death, and the mature,
hexagonal arrangement of the ommatidial cells becomes manifest
(Fig. 2C). In pupal eyes that
overexpress crbintra, the number of IOCs is increased, and
sorting of these cells fails to occur in many instances. As a consequence,
even at
42% p.d., there are too many IOCs [7.4 IOCs/ommatidium (total
number of ommatidia counted: 495), in comparison with 4.9 IOCs/ommatidium in
wild-type eyes (total number counted: 50 ommatidia)]. Many of the surplus IOCs
are aligned side-by-side instead of end-to-end, so that two cell rows are
found between many ommatidial cell clusters
(Fig. 2D). The secondary and
tertiary pigment cells are often arranged `astrally': four cells, instead of
the usual three, surround a bristle cell (compare
Fig. 2C with 2D, arrowheads).
As a result, the ommatidia adopt a square rather than a hexagonal shape, as
also observed in SEM images of adult eyes (see
Fig. 1B,B'). Ommatidia
with one additional cone cell (11/495 ommatidia) or primary pigment cell
(66/495) per ommatidium are also seen, albeit less frequently.
|
|
Embryos that overexpress crbintra develop multilayered
epithelia, in which components of the zonula adherens (ZA), such as the
homophilic cell-adhesion molecule DE-cadherin, are dispersed along the lateral
membranes instead of being concentrated in the ZA
(Klebes and Knust, 2000). To
find out whether the failure to properly localise IrreC-rst and sort IOCs in
eye discs overexpressing crbintra is the result of a
disruption of epithelial structure and/or misdistribution of DE-cadherin, we
analysed the structure of the epithelium and the distribution of DE-cadherin.
Persistent expression of crbintra indeed disrupts the
continuity of the DE-cadherin layer at the boundary between primary pigment
cell and IOC, and between the IOCs themselves (compare
Fig. 3B with 3H). By contrast,
DE-cadherin localisation is not affected in irreC-rst mutant eye
discs (Fig. 3E), suggesting
that DE-cadherin acts upstream of IrreC-rst localisation. As both DE-cadherin
and IrreC-rst are misdistributed in
GMR-Gal4>UAS-crbintra pupal eye discs at the time when
cell sorting occurs, we wondered whether the two proteins colocalise to the
ZA. Indeed, we found that the two proteins do colocalise apically
(Fig. 4A-F). In eye discs that
overexpress crbintra, however, partial colocalisation is
observed at the time when cell sorting occurs
(Fig. 3G-I), but at all stages
both proteins are restricted to apical regions
(Fig. 4G-L). However, at 42% of
p.d., both proteins exhibit a nearly wild-type pattern of expression, being
concentrated along the apical perimeter of the cells
(Fig. 2D,
Fig. 3L). These data thus
suggest that crbintra overexpression disturbs the
continuous apical distribution of DE-cadherin precisely at the time when cell
rearrangements occur, but, unlike the case in the embryo, it does not markedly
affect either apicobasal polarity or the overall structure of the epithelial
tissue.
|
|
Assembly of the apical belt of DE-cadherin is a prerequisite for the correct distribution of IrreC-rst
To test the idea that a continuous belt of DE-cadherin in the apical
regions of the cells is required for the correct localisation of IrreC-rst, we
analysed IrreC-rst expression in clones mutant for a putative null allele of
its coding gene shotgun (shgIH)
(Godt and Tepass, 1998;
Gonzalez-Reyes and St Johnston,
1998
), which produce no protein detectable with DCAD1
(Oda et al., 1998
) and in
pupal discs that overexpressed DE-cadherin (GMR-Gal4>UAS-DE-Cad).
Loss of shg prevents the accumulation of IrreC-rst at all membranes
(Fig. 6A-C), while persistent
expression of DE-cadherin leads to a patchy distribution of
-catenin,
another component of the adherens junction
(Fig. 6D-F). IrreC-rst becomes
mislocalised during the stage when cell sorting occurs, but colocalises with
-catenin in many of the patches at the membrane between primary pigment
cells and IOCs, and can also be detected at the borders between IOCs
(Fig. 6D-F). The defects in
cell sorting are milder than in discs overexpressing Crbintra (not
shown).
|
To summarise, IrreC-rst is colocalised with DE-cadherin in epithelial cells
of pupal eye discs, and misdistribution of adherens junction components
induces the mislocalisation of IrreC-rst, which then affects sorting of IOCs.
However, although DE-cadherin forms a continuous belt in the apical regions of
all cells (including all IOCs) in wild-type discs, IrreC-rst colocalises with
DE-cadherin only at the border between 1° pigment cells and IOCs
(Fig. 3A-C). What factor(s)
might be responsible for the spatial restriction of IrreC-rst to this border?
It has recently been shown that the removal of Notch or
Delta function during cell-sorting results in the ubiquitous
distribution of IrreC-rst to all plasma membranes and the prevention of
programmed cell death (Gorski et al.,
2000). We analysed whether this might be the result of defective
DE-cadherin localisation. Antibody staining reveals no influence of
Notch on the continuous apical localisation of DE-cadherin, but shows
that IrreC-rst now colocalises with the latter on all plasma membranes of the
IOCs (Fig. 6J-L). This suggests
that Notch acts downstream of DE-cadherin in the control of IrreC-rst
localisation. It is therefore tempting to speculate that it is the Notch
pathway, which provides local signalling between the lattice cells to direct
cell death (Miller and Cagan,
1998
), that prevents the accumulation of IrreC-rst at the borders
between IOCs and thus restricts its localisation to the 1°/IOC cell
boundary.
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Discussion |
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We were particularly interested in the relationship between the
localisation of DE-cadherin, a component of the zonula adherens (ZA) and
IrreC-rst. We show that in wild-type discs IrreC-rst colocalises with
DE-cadherin at the 1°/IOC border in the apical ZA of the cell and that
removal of DE-cadherin completely abolishes IrreC-rst accumulation. Nothing is
yet known about how IrreC-rst may integrate into the ZA at this border. In
vertebrates, the Ca++-independent cell adhesion molecule nectin, a
transmembrane protein of the immunoglobulin superfamily, has been implicated
in the organisation of cadherin-based adherens junctions, tight junctions and
synapses (reviewed by Takai and Nakanishi,
2003). It is recruited into cadherin-based adherens junctions
through interactions with the PDZ domain of l-afadin, an F-actin-binding
protein (Takahashi et al.,
1999
). Intriguingly, the C-terminal sequence of IrreC-rst (T-A-V)
matches the consensus binding site for class I PDZ domains (S/T-X-V)
(Harris and Lim, 2001
).
Interestingly, the protein encoded by the mutant allele
irreC-rstCT, which lacks the C-terminal 175 amino acids of
the wild-type form (Reiter et al.,
1996
), is no longer recruited into the ZA
(Fig. 4G-I). It is, however,
unlikely that IrreC-rst acts as a general adhesion molecule in IOCs of pupal
eye discs, because the epithelial tissue structure is stable in the absence of
irreC-rst function, as deduced from the formation of the continuous
apical belt of DE-cadherin in irreC-rst mutants (see
Fig. 4G).
The continuous belt of DE-cadherin can be disrupted by a number of
different genetic conditions, such as overexpression of the membrane-bound
intracellular domain of Crumbs, of DE-cadherin itself, or of a
dominant-negative version of the monomeric GTPase Rho1. Overexpression of the
membrane-bound intracellular domain of Crumbs in embryonic epithelia has
previously been shown to lead to a redistribution of DE-cadherin throughout
the plasma membrane and the formation of multilayered tissues
(Grawe et al., 1996;
Klebes and Knust, 2000
). By
contrast, IOCs overexpressing Crbintra exhibit a fragmented
DE-cadherin belt, which remains localized in the apical zone of the cells, and
apicobasal organisation and tissue integrity are not affected. This suggests
that IOCs may contain additional adhesion components which are independent of,
or less affected by, Crb. Support for this view comes from the phenotype of
discs lacking crb function, in which the apical belt of DE-cadherin
expression is fragmented, yet there is no major effect on polarity or adhesion
of the epithelium, the cells undergo nearly normal sorting and IrreC-rst is
still restricted to the membrane at the 1°/IOC border (N.G. and E.K.,
unpublished). Overexpression of Crbintra
ERLI does not
interfere with sorting, suggesting that a protein complex similar to the one
that controls apicobasal polarity in embryonic epithelia (which includes
Stardust, DPATJ and D-Lin7) contributes to the development of the dominant
phenotype.
Overexpression of DE-cadherin similarly results in the fragmentation of the
adhesion belt and defects in cell sorting. In various tissues, overexpression
of full-length DE-cadherin can also reduce Wingless signalling by sequestering
Armadillo from the cytoplasmic pool, thus making it unavailable to transduce
the Wingless signal (Sanson et al.,
1996). However, we can exclude the possibility that the defects in
sorting are the result of a suppression of Wingless signalling. Inactivation
of components of the Wingless pathway in eye imaginal discs induces the
initiation of ectopic morphogenetic furrows
(Ma and Moses, 1995
;
Treisman and Rubin, 1995
), and
this phenotype was not observed upon overexpression of DE-cadherin.
Overexpression of DE-cadherin in eye discs therefore seems to interfere with
adhesion, rather than Wingless signalling.
Rho GTPases play central roles in the organisation of the actin
cytoskeleton and in cell adhesion (reviewed by
Hall, 1998;
van Aelst and Symons, 2002
).
In mammals, inhibition of Rho activity results in the removal of cadherins
from epithelial cell junctions (Braga et
al., 1999
; Braga et al.,
1997
; Takaishi et al.,
1997
), while increased Rho activity induces an invasive and
metastatic phenotype (Schmitz et al.,
2000
). Members of the Rho GTPase family are recruited into the
adherens junctions by direct interactions with junctional components. Thus, in
Drosophila, Rho1 localises to the adherens junctions and interacts
directly with
-catenin and p120ctn, a homologue of
ß-catenin. As in pupal epithelia expressing a dominant-negative form of
Rho1, Rho1 mutant embryos exhibit a diffuse distribution of
components of the ZA, such as DE-cadherin and
- and ß-catenin
(Magie et al., 2002
). Rho1 may
either act directly on the accumulation of cadherins at the junctions, or
indirectly by recruiting accessory proteins, which then modulate the amounts
or activity of junctional and/or cytoskeletal proteins. Rho1 plays a different
role in tracheal epithelia insofar as its inactivation does not disrupt
DE-cadherin localisation, but rather interferes with the formation of the
apical surface and the tracheal lumen (Lee
and Kolodziej, 2002
).
Although it is evident that DE-cadherin plays a crucial role in the
accumulation of IrreC-rst at the adherens junctions, other mechanisms are
required to explain the asymmetric localisation and restriction of the latter
to the 1°/IOC boundary. Reiter et al.
(Reiter et al., 1996) have
speculated that an as yet unknown ligand expressed in the primary pigment cell
may account for this restricted accumulation. As an alternative - but not
mutually exclusive - model, we suggest that signalling between the IOCs,
mediated by Notch, which is expressed in IOCs during pupal development
(Kooh et al., 1993
), prevents
the accumulation of IrreC-rst at their borders. Interplay between adhesion and
signalling molecules also directs other processes in which cellular
polarisation is involved in tissue remodelling. The growth of the wing
imaginal disc along the proximodistal axis, for example, is the result of cell
shape changes and cell rearrangements during pupal development, which are
controlled by the atypical cadherins Fat and Dachsous, as well as
Four-Jointed, which is assumed to be a secreted molecule. This process, in
turn, is responsible for the asymmetric localisation of components that
control planar polarity, such as Frizzled, Dishevelled or Strabismus, which
serves to ensure that bristles and hairs adopt a common orientation (for
reviews, see Adler, 2002
;
Eaton, 2003
). During germ band
elongation in the Drosophila embryo, adherens junction remodelling in
intercalating ectodermal cells is facilitated by the polarised expression of
non-muscle myosin II at the anteroposterior and of Bazooka at the dorsoventral
cell boundaries (Bertet et al.,
2004
; Zallen and Wieschaus,
2004
). Future experiments will demonstrate whether cell sorting in
pupal eye discs makes use of any of the components known to be involved in
these processes.
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ACKNOWLEDGMENTS |
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