Howard Hughes Medical Institute, Waksman Institute and Department of Molecular Biology and Biochemistry, Rutgers The State University of New Jersey, Piscataway, NJ 08854, USA
* Author for correspondence (e-mail: irvine{at}waksman.rutgers.edu)
Accepted 27 June 2005
![]() |
SUMMARY |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: Compartment, Boundary, Fringe, Capulet, Drosophila
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The specification of AP and DV compartments is initiated by the restricted
expression of transcription factors Engrailed/Invected (En), which is
expressed by posterior cells, and Apterous (Ap), which is expressed by dorsal
cells (Blair et al., 1994;
Diaz-Benjumea and Cohen, 1993
;
Lawrence and Struhl, 1982
;
Morata and Lawrence, 1975
;
Simmonds et al., 1995
;
Tabata et al., 1995
;
Zecca et al., 1995
). AP
compartmentalization also requires Hedgehog (Hh)-mediated signaling from
posterior cells to anterior cells (Blair
and Ralston, 1997
; Dahmann and
Basler, 2000
; Rodriguez and
Basler, 1997
). Although the molecular targets remain unknown,
genetic manipulation that results in Hh pathway activation can cause cells to
sort from posterior to anterior, whereas manipulation that results in a loss
of Hh signaling can cause cells to sort from anterior to posterior. These
observations imply that Hh signaling influences compartmentalization by
promoting an anterior-type cell affinity.
Ap influences DV compartmentalization through at least two distinct
mechanisms, which appear to act sequentially. First, Ap promotes the dorsal
expression of Tartan (Trn) and Capricious (Caps). A role for Trn and Caps has
been inferred from the observation that ectopic expression of these proteins
can cause ventral cells to sort to the DV compartment border
(Milan et al., 2001).
Loss-of-function mutations in these genes do not affect compartmentalization,
but it is thought that they might act redundantly with other factors
(Milan et al., 2001
). However,
Trn and Caps are expressed specifically by dorsal cells in the second larval
instar, when the DV compartment boundary forms, but in the third instar they
become expressed in ventral lateral cells and stop being expressed by dorsal
medial cells. Thus, any role of Trn and Caps in DV compartmentalization must
be transient.
A second mechanism by which Ap influences compartmentalization is through
its influence on Notch signaling
(Micchelli and Blair, 1999;
O'Keefe and Thomas, 2001
;
Rauskolb et al., 1999
). Ap
promotes the dorsal-specific expression of a Notch ligand, Serrate (Ser), and
a Notch glycosyltransferase, Fringe (Fng)
(Couso et al., 1995
;
Irvine and Wieschaus, 1994
).
Modification of Notch by Fng both inhibits Ser-to-Notch signaling, restricting
Ser to signaling from dorsal cells to ventral cells, and potentiates
Delta-to-Notch signaling, enabling the activation of Notch by the Delta ligand
in dorsal cells (Fig. 1A)
(Fleming et al., 1997
;
Haines and Irvine, 2003
;
Panin et al., 1997
). The
action of Fng thereby positions and restricts a stripe of Notch activation
along the DV border. Notch signaling is required for DV compartmentalization
(Micchelli and Blair, 1999
;
Rauskolb et al., 1999
), but
there are crucial differences between the action of Notch at the DV boundary
and that of Hh at the AP boundary. Signaling between dorsal and ventral
compartments is bidirectional, rather than unidirectional. Additionally,
neither ectopic activation of Notch nor loss of Notch activation cause
directed changes in cell location
(Micchelli and Blair, 1999
;
Milan and Cohen, 2003
;
Rauskolb et al., 1999
).
Rather, when Notch activation is disrupted, cells can intermingle in either
direction, irrespective of their genotype or DV identity.
The influence of Notch indicates that it cannot affect DV
compartmentalization simply by promoting a compartment-specific cell affinity
on its own, and different models have been proposed to explain its role
(Irvine and Rauskolb, 2001;
Micchelli and Blair, 1999
;
Milan and Cohen, 1999
;
Milan and Cohen, 2003
;
O'Keefe and Thomas, 2001
;
Rauskolb et al., 1999
). Two
models are based on the conventional view that compartmentalization requires
the establishment of distinct, compartment-specific cell affinities. In one
version (Micchelli and Blair,
1999
), Notch activation confers a distinct boundary cell affinity,
which is modified by the presence of Ap in dorsal cells into a dorsal-boundary
affinity. This model was based on loss-of-function experiments, and would
appear to be inconsistent with the results of gain-of-function experiments: if
Notch activation conferred a boundary-type cell affinity, then clones of cells
in which Notch was constituitively activated would be expected to sort to the
DV boundary, but this is not the case
(Milan and Cohen, 2003
;
Rauskolb et al., 1999
). A
related model (Milan and Cohen,
2003
) gets around this problem by proposing that Notch be
considered `permissive' and Ap `instructive' for the specification of a
distinct cell affinity. Thus, it shares the proposal that Ap and Notch act
combinatorially to specify a dorsal-boundary cell affinity, but differs in
that Notch activation alone is proposed to be insufficient to specify a
distinct cell affinity that can influence compartmentalization.
By contrast, we have proposed a completely different model, in which Notch
activation does not influence compartmentalization by contributing to dorsal-
or ventral-type cell affinities, but rather creates a fence
(Irvine and Rauskolb, 2001;
Rauskolb et al., 1999
), which
we define as a property or behavior of cells at the border that keeps them
from intermingling. In support of this model, we note that an ectopic stripe
of Notch activation created, for example, by mutation or
mis-expression of Fng in clones of cells can be sufficient to separate
cells, even though cells on both sides of the border are all dorsal or are all
ventral, and even though cells on both sides of the border have similar levels
of Notch activation (O'Keefe and Thomas,
2001
; Rauskolb et al.,
1999
) (Fig. 1B).
These observations are inconsistent with models that propose a requirement for
a Notch-independent influence of Apterous on cell affinity, but they have been
disputed (Milan and Cohen,
1999
; Milan and Cohen,
2003
).
Thus, in the first section of this paper, we revisit the issue of the
sufficiency of Notch activation in separating cells, providing both additional
data in support of the fence model, and an alternative explanation for the
observations of Milan and Cohen (Milan and
Cohen, 1999; Milan and Cohen,
2003
). We then show that cells at the DV boundary have a
distinctive shape, and that F-actin accumulates at the adherens junctions at
the DV interface. Genetic manipulation establishes that a stripe of Notch
activation is both necessary and sufficient for these phenotypes. The
observation of a distinct, Notch-dependent boundary morphology further
supports the fence hypothesis, and also suggests that a non-transcriptional
branch of the Notch pathway participates in DV compartmentalization. Finally,
we show that a regulator of actin polymerization exhibits a distinct
requirement at the DV compartment boundary, consistent with the possibility
that Notch influences compartmentalization via its ability to modulate
F-actin. Together, our observations emphasize that DV compartmentalization is
mechanistically distinct from AP compartmentalization, and that the
establishment of a separation fence rather than specific compartmental
affinities provides the best explanation for DV compartmentalization.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Depending on the availability and species of antibodies available, dorsal
or anterior cells were marked in some experiments by enhancer trap lines; we
used ap-lacZrQ107, ap-lacZrK568 and
ci-lacZ. UAS--Cat:GFP arm-Gal4 was used to detect
-catenin (Oda and Tsukita,
1999
).
Stocks used for making clones included:
Immunostaining and image analysis
Imaginal discs were fixed for 15 minutes in 2% formaldehyde (methanol-free)
in Ringer's solution (120 mM NaCl, 1.88 mM KCl, 2.38 mM NaHCO3,
0.06 mM NaH2PO4, 0.82 mM CaCl2) and then
stained immediately. Primary antibodies used were rat anti-dLMO (Beadex) (at
1:100, S. Cohen, Heidelberg, Germany), mouse anti-WG 4D4 [at 1:400,
Developmental Studies Hybridoma Bank (DSHB)], rat anti-E-cadherin DCAD2 (at
1:20, DSHB), mouse anti-Armadillo N2 7A1 (at 1:100, DSHB), mouse anti-Delta
C594.9B (at 1:50, DHSB), mouse anti-Ena 5G2 (1:50, DSHB), mouse
anti-phosphotyrosine PY20 (1:300, Covance), rabbit anti-ß-gal (at 1:20,
ICN), mouse anti-En 4D9 (at 1:200, DHSB), mouse anti-alpha tubulin-FITC (at
1:50, Sigma F2168). Secondary antibodies were from Molecular Probes and
Jackson Immunoresearch Laboratories. F-actin labeling was performed after
immunostaining, using 488- or 546-conjugated phalloidin (Molecular Probes) at
a 1:10 dilution for 40 minutes at room temperature.
Discs were analyzed by the acquisition of serial optical sections on a Leica TCS SP confocal microscope. Adjacent sections, including the apical disc surface, were combined by maximum projection with Leica software. In those instances where the curvature of the disc did not allow good visualization of the entire apical surface through a single maximum projection, groups of 10-30 sections (representing 1-6 µm) were combined by maximum projection, and then a composite image of the apical surface was created by using the layers feature of Adobe Photoshop. Similarly, because the nuclei are basal to the apical actin cytoskeleton, for purposes of illustration, we prepared images that combine projections through basal regions to show nuclear markers with projections through apical regions to show apical F-actin.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
However, the ability of Fng to effect Notch activation varies across the
wing (Irvine and Wieschaus,
1994; Milan and Cohen,
2000
), presumably because Fng does not activate Notch directly,
but rather influences its sensitivity to ligands, which are themselves
distributed in a dynamic, spatial pattern. Thus, a trivial explanation for the
observation that edges of Fng expression are more irregular than edges of Ap
expression (Milan and Cohen,
2003
) is simply that they effect different levels of Notch
activation. Consistent with this, Fng clone edges near the DV boundary tend to
be smoother than clone edges that are far from the DV boundary (data not
shown). Indeed, the argument that Notch activation is not sufficient for
compartmentalization (Milan and Cohen,
1999
; Milan and Cohen,
2003
) relies on the assumption that expression of Wingless (Wg),
which has been widely used as a marker of Notch activation in the wing, is a
reliable indicator of the quality of activation required for
compartmentalization. To evaluate this assumption, we partially compromised
Notch signaling using a temperature-sensitive allele of Notch, and
then assayed both Wg expression, and the interface between dorsal and ventral
cells (Fig. 2). At intermediate
temperatures, expression of Wg remains detectable even as the DV interface
becomes irregular (Fig. 2B).
Thus, compartmentalization appears to require a level or quality of Notch
activation that is distinct from that required for Wg expression.
|
|
|
|
Interestingly, F-actin staining reveals that the AP boundary is not as
straight as the DV boundary during early third instar
(Fig. 5A,B), but does
straighten out later in third instar (Fig.
5C-E) (Blair,
1992). Elevation of F-actin is also sometimes (18/120 discs)
observed at the AP boundary, but this occurs preferentially at later stages,
is consistently weaker than at the DV boundary, and in almost all cases only
extends along part of the AP boundary, mostly in dorsal cells
(Fig. 5 and data not
shown).
Notch regulates the F-actin cytoskeleton in the wing
To determine whether the distinct features of the DV boundary require
positional information at the juxtaposition of dorsal and ventral cells, or
instead are regulated by Notch activation, we examined F-actin under
conditions where the pattern of Notch activation was altered. Elimination of
normal Notch activation by expression of Fng in ventral cells abolishes the
distinctive features of cellular morphology and F-actin organization at the
interface between dorsal and ventral cells
(Fig. 6A). These features of
the DV interface are also eliminated by downregulation of Notch function in
Nts animals (data not shown). Thus, Notch activation is
required for F-actin organization and cellular morphology at the DV boundary.
Importantly, the ectopic Notch activation stripe generated by high-level
expression of Fng in ventral cells (i.e. in UAS-fng ptc-Gal4 animals)
is consistently associated with induction of a DV boundary-like cell
morphology, F-actin organization and upregulation of Ena protein
(Fig. 6A and data not shown).
Because this now occurs entirely within ventral cells, Notch activation must
also be sufficient for the regulation of these processes. Lower level Fng
expression in clones of cells (i.e. in UAS-fng AyGal4 animals) was
less effective at influencing F-actin organization and cell morphology, but,
as noted above, the edges of these clones are sometimes irregular.
Importantly, Delta-expressing clones, which are generally rounder than
Fringe-expressing clones, are often associated with an upregulation of F-actin
and a smooth interface at the adherens junctions (15/25 dorsal clones, and
27/51 total clones, exhibited upregulation of F-actin)
(Fig. 6B,C). The change in
F-actin staining does not appear to be a simple consequence of differences in
cell affinity, because clones of cells mutant for the protocadherin gene
fat (Mahoney et al.,
1991) are not associated with upregulation of F-actin
(Fig. 6E).
|
Influence of Actin-regulatory proteins on DV compartmentalization
To evaluate the functional significance of F-actin structures in DV
compartmentalization, we examined the consequences of mutation or ectopic
expression of actin regulatory proteins. The Abl gene encodes a
tyrosine kinase that interacts genetically with Notch in axon guidance
(Crowner et al., 2003;
Giniger, 1998
), but neither
mutation nor ectopic expression of Abl exerted detectable influences
on DV compartmentalization. Ena is a substrate for Abl, and also interacts
genetically with Abl, but clones of cells mutant for a hypomorphic
allele did not affect DV compartmentalization, and clones of cells mutant for
a null allele could not be recovered. Conversely, mutations in the Profilin
homolog chickadee, or expression of dominant-negative forms of the
actin-regulatory G proteins Rac, Rho or Cdc42, resulted in varying degrees of
disturbance to the DV boundary, but only under conditions that also resulted
in more gross defects like cell death, cells dropping out of the epithelium,
invasive behavior, and/or disturbance of the AP compartment boundary (not
shown). These defects made it difficult to assess the significance of affects
of these mutations on DV compartmentalization.
However, mutations in capulet (capt, also known as
act up) consistently and specifically disrupted the DV compartment
boundary under partial loss-of-function conditions. capt is a
Drosophila cyclase-associated protein
(Baum et al., 2000;
Benlali et al., 2000
), which
interacts genetically with Abl to influence axon guidance
(Wills et al., 2002
), and
restricts apical actin polymerization in epithelial cells
(Baum and Perrimon, 2001
). When
examined only two days after clone induction, no cell death or loss from the
disc epithelium could be detected in capt mutant clones.
Additionally, two-day-old capt clones failed to disturb the AP
compartment boundary (Fig. 7C; 0/39 clones that touch the AP interface, as judged by the expression of
Engrailed (En), were associated with an irregular boundary). Importantly then,
two-day-old capt mutant clones exhibited strong and consistent
disturbances of the DV compartment boundary
[Fig. 7A,B; 27/82 clones that
touched the DV interface, as judged by expression of the dorsal marker Beadex
(Bx, also known as dLMO) (Weihe et al.,
2001
), were associated with an irregular boundary]. This
presumably reflects a hypomorphic situation due to perdurance of capt
gene product, as three days after clone induction the DV compartment boundary
was still disturbed, but a fraction of mutant cells also appeared to be
undergoing apoptosis or dropping out of the disc epithelium. Thus, although
capt has a general role in epithelial integrity,
reduction-of-function conditions reveal a particular requirement for
capt at the DV compartment boundary.
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Modulation of the actin cytoskeleton by the Notch pathway
The polarization of F-actin accumulation effected by Notch activation at
the DV boundary cannot easily be accounted for purely by the transcriptional
regulation of target genes associated with Notch activation. In the context of
the normal DV boundary, or an ectopic boundary associated with altered Fng
expression, a rectangular cell at the boundary has three neighbors with
similar levels of Notch activation, but F-actin is elevated along only one of
these cell interfaces (Fig. 1).
In the case of ectopic Delta expression, Notch activation is actually
inhibited inside of Delta-expressing clones through autonomous inhibition
(de Celis and Bray, 1997;
Doherty et al., 1996
;
Micchelli et al., 1997
), and
so is now asymmetric with respect to the clone boundary, yet it still effects
a similar modulation of F-actin. The common feature of the cellular interface
at which F-actin is upregulated in all cases is that it is the cellular
interface at which most Notch-ligand interaction is actually occurring. This
leads us to suggest that F-actin accumulation might be polarized through an
alternate Notch pathway that impinges on the actin cytoskeleton. This
inference is consistent with the observation that forms of Notch that are
constituitively activated for transcriptional pathways do not result in a
general, autonomous upregulation of F-actin.
The possibility of links from Notch or its ligands to the actin
cytoskeleton that do not involve the canonical Notch transcriptional pathway
has been suggested previously, based on studies of their influence on axon
guidance, neurite or filopodial extension, and keratinocyte motility
(Crowner et al., 2003;
De Joussineau et al., 2003
;
Giniger, 1998
;
Lowell and Watt, 2001
). The
nature of this alternate pathway or pathways is not clear. In the context of
the influence of Notch on axon guidance in the Drosophila embryo,
this alternate pathway is characterized by genetic interactions with
Abl, and a lack of genetic interactions with the Notch pathway
transcription factor Suppressor of Hairless [Su(H)]
(Crowner et al., 2003
;
Giniger, 1998
). Although
Abl mutations do not noticeably affect DV compartmentalization,
Abl mutants in general have relatively mild effects, presumably
because Abl is partially redundant
(Gertler et al., 1989
), and
the elevation in phosho-tyrosine and Ena staining at the DV boundary is
intriguing in light of potential links between Notch and Abl.
Sequential mechanisms in DV compartmentalization
Rather than a single mechanism for compartmentalization, studies of the DV
boundary suggest that a series of distinct strategies affect what, by lineage
analysis, appears to be a constant boundary. Trn and Caps, are expressed
specifically in dorsal cells during the second larval instar, when the
boundary first forms. Ectopic expression of these proteins can cause ventral
cells to sort to and associate with dorsal cells
(Milan et al., 2001), but
their contribution to compartmentalization must be transient, as their
dorsal-specific expression is lost during early third instar. Elevated F-actin
staining at the DV boundary could not be consistently detected during second
instar, was clearly visible from early through mid-third instar, but
disappeared at late third instar. Thus, the role of the F-actin-dependent
fence might also be transient. At late third instar, cells near the DV
boundary stop proliferating (Blair,
1993
; Johnston and Edgar,
1998
; O'Brochta and Bryant,
1985
). As the arrangement of cells in imaginal discs is largely a
function of growth rather than movement, this cessation of proliferation
presents a third potential mechanism for compartmentalization, which could be
important at late stages.
Models for the role of Notch in DV compartmentalization
It has generally been assumed that compartmentalization is effected by the
establishment of differential cell affinities, which result in cells sorting
to their respective sides of a compartment boundary
(Blair, 2003b;
McNeill, 2000
). Although this
paradigm fits well with studies of AP compartmentalization, it is not easy to
reconcile with studies of DV compartmentalization, given that Notch is
activated and required on both sides of the compartment boundary, that neither
mutation nor ectopic activation of Notch causes directed changes in cell
location, that the requirement for Notch is non-autonomous, and that the
requirement for Notch does not depend on the dorsal or ventral identity of a
cell. Models that have proposed that Notch influences DV compartmentalization
by affecting a compartment-specific cell affinity have required that it act in
conjunction with Ap (Micchelli and Blair,
1999
; Milan and Cohen,
2003
). The crucial failing of such models, in our view, is that
they cannot explain how a compartmental separation of cells is achieved by the
ectopic Notch activation associated with a mutation of fng, or
ectopic expression of Fng, Serrate or Delta, as in all of these cases cells on
both sides of the boundary are identical with respect to the presence or
absence of Ap.
An alternative hypothesis is that Notch activation influences a property or behavior of cells at the boundary in a way that prevents them from intermingling, which we refer to as a fence. The determination that Notch signaling effects a polarized elevation of F-actin and Ena supports this hypothesis, as it demonstrates that Notch can polarize the actin cytoskeleton in conjunction with its ability to separate cells, and that this influence of Notch is independent of the dorsal or ventral identity of the cell. Additionally, the bidirectional and non-autonomous disruptions of the compartment boundary effected by capt mutant clones are consistent with the inference that compartmentalization involves an F-actin-dependent fence. When the fence is broken, cells can intermix in either direction, irrespective of their DV identity. By contrast, it is not clear how the non-autonomous affects of capt mutant clones could be reconciled with models that postulate a compartment-specific cell affinity.
The possibility of a non-transcriptional influence of Notch on DV
compartmentalization, as suggested above for its influence on F-actin, is
appealing because it could explain the observation that Fng can influence
compartmentalization even when co-expressed with N-intra
(Rauskolb et al., 1999).
Loss-of-function studies have provided mixed results as to the requirements
for Notch transcriptional pathways in DV compartmentalization. Clones of cells
mutant for a hypomorphic allele of Su(H), Su(H)SF8,
respect the compartment boundary, even though transcriptional targets are
affected (Micchelli and Blair,
1999
). However, this is not a null situation for Su(H),
and we would predict that at a minimum, a Notch transcriptional pathway would
be required at the DV boundary to maintain the expression of Notch ligands
(Fig. 1A). Requirements for
transcriptional mediator proteins confirm that transcription is required for
DV compartmentalization (Janody et al.,
2003
), but a role for a transcriptional Notch pathway does not
preclude a parallel role for a non-transcriptional pathway.
How might a compartmentalization fence be constructed?
The molecular nature of the compartmentalization fence is not yet clear,
but some possibilities can be suggested. One model is based on the similarity
of the F-actin stripe at the DV boundary to a prominent F-actin cable detected
along the interface between leading edge cells and amnion-serosa cells during
dorsal closure of the Drosophila embryo
(Dequier et al., 2001). The
F-actin cable and associated proteins are thought to help keep dorsal
epidermal cells in register as they move, through actin-myosin-based
contraction and/or influences on the protrusive behavior of filopodia
(Jacinto et al., 2002
;
Kiehart et al., 2000
). Similar
processes could maintain a smooth separation between cells at the DV
compartment boundary. Intriguingly, genetic studies have suggested a potential
role for Notch in dorsal closure that does not involve Su(H)
(Zecchini et al., 1999
). The
distinct requirement for a regulator of actin polymerization, capt,
at the DV boundary is consistent with the hypothesis that the elevated F-actin
detected at the DV boundary plays a crucial role in compartmentalization. In
this view, the F-actin cable would be a physical manifestation of the
Notch-dependent separation fence.
An alternative possibility is suggested by the observations Notch and its
ligands can, at least in cultured cell assays, act as cell adhesion molecules
(Fehon et al., 1990), and that
association of Notch with its ligands can promote cleavage of both molecules
(Bland et al., 2003
;
Kidd et al., 1998
;
Lecourtois and Schweisguth,
1998
; Struhl and Adachi,
1998
). Thus, while loss- and gain-of-function studies of Notch
ligands do not support the possibility that they act as compartment-specific
cell adhesion molecules (Rauskolb et al.,
1999
), we suggest that cleavage of Notch and/or its ligands might
act as a boundary-specific de-adhesion mechanism. Boundary-specific
de-adhesion, rather than compartment-specific adhesion, has been suggested as
a possible mechanism for Eph-Ephrin-mediated cell separation
(Cooke and Moens, 2002
). In
this model, the influence on F-actin might be a secondary consequence of the
primary separation mechanism. Alternatively, because the cytoplasmic domains
of Notch and its ligands have been reported to associate with proteins that
can impinge on actin organization
(Giniger, 1998
;
Six et al., 2004
;
Wright et al., 2004
), Notch or
ligand cleavage might be a direct mechanism for modulating F-actin.
![]() |
ACKNOWLEDGMENTS |
---|
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Baum, B. and Perrimon, N. (2001). Spatial control of the actin cytoskeleton in Drosophila epithelial cells. Nat. Cell Biol. 3,883 -890.[CrossRef][Medline]
Baum, B., Li, W. and Perrimon, N. (2000). A cyclase-associated protein regulates actin and cell polarity during Drosophila oogenesis and in yeast. Curr. Biol. 10,964 -973.[CrossRef][Medline]
Benlali, A., Draskovic, I., Hazelett, D. J. and Treisman, J. E. (2000). act up controls actin polymerization to alter cell shape and restrict Hedgehog signaling in the Drosophila eye disc. Cell 101,271 -281.[CrossRef][Medline]
Blair, S. S. (1992). Engrailed expression in the anterior lineage compartment of the developing wing blade of Drosophila. Development 115,21 -33.[Abstract]
Blair, S. S. (1993). Mechanisms of compartment
formation: evidence that non-proliferating cells do not play a critical role
in defining the D/V lineage restriction in the developing wing of Drosophila.
Development 119,339
-351.
Blair, S. S. (2003a). Genetic mosaic techniques
for studying Drosophila development. Development
130,5065
-5072.
Blair, S. S. (2003b). Lineage compartments in Drosophila. Curr. Biol. 13,R548 -R551.[CrossRef][Medline]
Blair, S. S. and Ralston, A. (1997).
Smoothened-mediated Hedgehog signalling is required for the maintenance of the
anterior-posterior lineage restriction in the developing wing of Drosophila.
Development 124,4053
-4063.
Blair, S. S., Brower, D. L., Thomas, J. B. and Zavortink, M.
(1994). The role of apterous in the control of dorsoventral
compartmentalization and PS integrin gene expression in the developing wing of
Drosophila. Development
120,1805
-1815.
Bland, C. E., Kimberly, P. and Rand, M. D.
(2003). Notch-induced proteolysis and nuclear localization of the
Delta ligand. J. Biol. Chem.
278,13607
-13610.
Cooke, J. E. and Moens, C. B. (2002). Boundary formation in the hindbrain: Eph only it were simple. Trends Neurosci. 25,260 -267.[CrossRef][Medline]
Couso, J. P., Knust, E. and Martinez Arias, A. (1995). Serrate and wingless cooperate to induce vestigial gene expression and wing formation in Drosophila. Curr. Biol. 5,1437 -1448.[CrossRef][Medline]
Crowner, D., Le Gall, M., Gates, M. A. and Giniger, E. (2003). Notch steers Drosophila ISNb motor axons by regulating the Abl signaling pathway. Curr. Biol. 13,967 -972.[CrossRef][Medline]
Dahmann, C. and Basler, K. (2000). Opposing transcriptional outputs of Hedgehog signaling and engrailed control compartmental cell sorting at the Drosophila A/P boundary. Cell 100,411 -422.[CrossRef][Medline]
de Celis, J. F. and Bray, S. (1997). Feed-back
mechanisms affecting Notch activation at the dorsoventral boundary in the
Drosophila wing. Development
124,3241
-3251.
De Joussineau, C., Soule, J., Martin, M., Anguille, C., Montcourrier, P. and Alexandre, D. (2003). Delta-promoted filopodia mediate long-range lateral inhibition in Drosophila. Nature 426,555 -559.[CrossRef][Medline]
Dequier, E., Souid, S., Pal, M., Maroy, P., Lepesant, J. A. and Yanicostas, C. (2001). Top-DER- and Dpp-dependent requirements for the Drosophila fos/kayak gene in follicular epithelium morphogenesis. Mech. Dev. 106, 47-60.[CrossRef][Medline]
Diaz-Benjumea, F. J. and Cohen, S. M. (1993). Interaction between dorsal and ventral cells in the imaginal disc directs wing development in Drosophila. Cell 75,741 -752.[CrossRef][Medline]
Doherty, D., Feger, G., Younger-Shepherd, S., Jan, L. Y. and Jan, Y. N. (1996). Delta is a ventral to dorsal signal complementary to Serrate, another Notch ligand, in Drosophila wing formation. Genes Dev. 10,421 -434.[Abstract]
Fehon, R. G., Kooh, P. J., Rebay, I., Regan, C. L., Xu, T., Muskavitch, M. A. T. and Artavanis-Tsakonas, S. (1990). Molecular interactions between the protein products of the neurogenic loci Notch and Delta, two EGF-homologous genes in Drosophila. Cell 61,523 -534.[CrossRef][Medline]
Fleming, R. J., Gu, Y. and Hukriede, N. A.
(1997). Serrate-mediated activation of Notch is
specifically blocked by the product of the gene fringe in the dorsal
compartment of the Drosophila wing imaginal disc.
Development 124,2973
-2981.
Gertler, F. B., Bennett, R. L., Clark, M. J. and Hoffmann, F. M. (1989). Drosophila abl tyrosine kinase in embryonic CNS axons: a role in axonogenesis is revealed through dosage-sensitive interactions with disabled. Cell 58,103 -113.[CrossRef][Medline]
Gertler, F. B., Comer, A. R., Juang, J. L., Ahern, S. M., Clark, M. J., Liebl, E. C. and Hoffmann, F. M. (1995). enabled, a dosage-sensitive suppressor of mutations in the Drosophila Abl tyrosine kinase, encodes an Abl substrate with SH3 domain-binding properties. Genes Dev. 9,521 -533.[Abstract]
Giniger, E. (1998). A role for Abl in Notch signaling. Neuron 20,667 -681.[CrossRef][Medline]
Haines, N. and Irvine, K. D. (2003). Glycosylation regulates Notch signalling. Nat. Rev. Mol. Cell Biol. 4,786 -797.[Medline]
Irvine, K. D. and Wieschaus, E. (1994). fringe, a Boundary-specific signaling molecule, mediates interactions between dorsal and ventral cells during Drosophila wing development. Cell 79,595 -606.[CrossRef][Medline]
Irvine, K. D. and Rauskolb, C. (2001). Boundaries in development: formation and function. Annu. Rev. Cell Dev. Biol. 17,189 -214.[CrossRef][Medline]
Jacinto, A., Wood, W., Woolner, S., Hiley, C., Turner, L., Wilson, C., Martinez-Arias, A. and Martin, P. (2002). Dynamic analysis of actin cable function during Drosophila Dorsal closure. Curr. Biol. 12,1245 -1250.[CrossRef][Medline]
Janody, F., Martirosyan, Z., Benlali, A. and Treisman, J. E.
(2003). Two subunits of the Drosophila mediator complex act
together to control cell affinity. Development
130,3691
-3701.
Johnston, L. A. and Edgar, B. A. (1998). Wingless and Notch regulate cell-cycle arrest in the developing Drosophila wing. Nature 394,82 -84.[CrossRef][Medline]
Kidd, S., Lieber, T. and Young, M. W. (1998).
Ligand-induced cleavage and regulation of nuclear entry of Notch in Drosophila
melanogaster embryos. Genes Dev.
12,3728
-3740.
Kiehart, D. P., Galbraith, C. G., Edwards, K. A., Rickoll, W. L.
and Montague, R. A. (2000). Multiple forces contribute
to cell sheet morphogenesis for dorsal closure in Drosophila. J.
Cell Biol. 149,471
-490.
Larkin, M. K., Holder, K., Yost, C., Giniger, E. and
Ruohola-Baker, H. (1996). Expression of constitutively active
Notch arrests follicle cells at a precursor stage during Drosophila oogenesis
and disrupts the anterior-posterior axis of the oocyte.
Development 122,3639
-3650.
Lawrence, P. A. and Struhl, G. (1982). Further studies of the engrailed phenotype in Drosophila. EMBO J. 1,827 -833.[Medline]
Lecourtois, M. and Schweisguth, F. (1998). Indirect evidence for Delta-dependent intracellular processing of notch in Drosophila embryos. Curr. Biol. 8, 771-774.[CrossRef][Medline]
Lowell, S. and Watt, F. M. (2001). Delta regulates keratinocyte spreading and motility independently of differentiation. Mech. Dev. 107,133 -140.[CrossRef][Medline]
Mahoney, P. A., Weber, U., Onofrechuk, P., Biessmann, H., Bryant, P. J. and Goodman, C. S. (1991). The fat tumor suppressor gene in Drosophila encodes a novel member of the cadherin gene superfamily. Cell 67,853 -868.[CrossRef][Medline]
McNeill, H. (2000). Sticking together and sorting things out: adhesion as a force in development. Nat. Rev. Genet. 1,100 -108.[CrossRef][Medline]
Micchelli, C. A. and Blair, S. S. (1999). Dorsoventral lineage restriction in wing imaginal discs requires Notch. Nature 401,473 -476.[CrossRef][Medline]
Micchelli, C. A., Rulifson, E. J. and Blair, S. S.
(1997). The function and regulation of cut expression on the wing
margin of Drosophila: Notch, Wingless and a dominant negative role for Delta
and Serrate. Development
124,1485
-1495.
Milan, M. and Cohen, S. M. (1999). Notch signaling is not sufficient to define the affinity boundary between dorsal and ventral compartments. Mol. Cell 4,1073 -1078.[CrossRef][Medline]
Milan, M. and Cohen, S. M. (2000). Temporal
regulation of apterous activity during development of the Drosophila wing.
Development 127,3069
-3078.
Milan, M. and Cohen, S. M. (2003). A
re-evaluation of the contributions of Apterous and Notch to the dorsoventral
lineage restriction boundary in the Drosophila wing.
Development 130,553
-562.
Milan, M., Weihe, U., Perez, L. and Cohen, S. M. (2001). The LRR proteins capricious and Tartan mediate cell interactions during DV boundary formation in the Drosophila wing. Cell 106,785 -794.[CrossRef][Medline]
Morata, G. and Lawrence, P. A. (1975). Control of compartment development by the engrailed gene in Drosophila. Nature 255,614 -617.[CrossRef][Medline]
O'Brochta, D. A. and Bryant, P. J. (1985). A zone of non-proliferating cells at a lineage restriction boundary in Drosophila. Nature 313,138 -141.[CrossRef][Medline]
O'Keefe, D. D. and Thomas, J. B. (2001).
Drosophila wing development in the absence of dorsal identity.
Development 128,703
-710.
Oda, H. and Tsukita, S. (1999). Dynamic features of adherens junctions during Drosophila embryonic epithelial morphogenesis revealed by a Dalpha-catenin-GFP fusion protein. Dev. Genes Evol. 209,218 -225.[CrossRef][Medline]
Panin, V. M., Papayannopoulos, V., Wilson, R. and Irvine, K. D. (1997). Fringe modulates Notch-ligand interactions. Nature 387,908 -912.[CrossRef][Medline]
Rauskolb, C., Correia, T. and Irvine, K. D. (1999). Fringe-dependent separation of dorsal and ventral cells in the Drosophila wing. Nature 401,476 -480.[CrossRef][Medline]
Rodriguez, I. and Basler, K. (1997). Control of compartmental affinity boundaries by hedgehog. Nature 389,614 -618.[CrossRef][Medline]
Schweisguth, F. (2004). Notch signaling activity. Curr. Biol. 14,R129 -R138.[CrossRef][Medline]
Simmonds, A. J., Brook, W. J., Cohen, S. M. and Bell, J. B. (1995). Distinguishable functions for engrailed and invected in anterior-posterior patterning in the Drosophila wing. Nature 376,424 -427.[CrossRef][Medline]
Six, E. M., Ndiaye, D., Sauer, G., Laabi, Y., Athman, R.,
Cumano, A., Brou, C., Israel, A. and Logeat, F.
(2004). The notch ligand Delta1 recruits Dlg1 at cell-cell
contacts and regulates cell migration. J. Biol. Chem.
279,55818
-55826.
Struhl, G. and Adachi, A. (1998). Nuclear access and action of notch in vivo. Cell 93,649 -660.[CrossRef][Medline]
Tabata, T., Schwartz, C., Gustavson, E., Ali, Z. and Kornberg,
T. B. (1995). Creating a Drosophila wing de novo, the role of
engrailed, and the compartment border hypothesis.
Development 121,3359
-3369.
Weihe, U., Milan, M. and Cohen, S. M. (2001). Regulation of Apterous activity in Drosophila wing development. Development 128,4615 -4622.[Medline]
Wills, Z., Emerson, M., Rusch, J., Bikoff, J., Baum, B., Perrimon, N. and Van Vactor, D. (2002). A Drosophila homolog of cyclase-associated proteins collaborates with the Abl tyrosine kinase to control midline axon pathfinding. Neuron 36,611 -622.[CrossRef][Medline]
Wright, G. J., Leslie, J. D., Ariza-McNaughton, L. and Lewis,
J. (2004). Delta proteins and MAGI proteins: an interaction
of Notch ligands with intracellular scaffolding molecules and its significance
for zebrafish development. Development
131,5659
-5669.
Zecca, M., Basler, K. and Struhl, G. (1995).
Sequential organizing activities of engrailed, hedgehog, and decapentaplegic
in the Drosophila wing. Development
121,2265
-2278.
Zecchini, V., Brennan, K. and Martinez-Arias, A. (1999). An activity of Notch regulates JNK signalling and affects dorsal closure in Drosophila. Curr. Biol. 9, 460-469.[CrossRef][Medline]
Related articles in Development:
|