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 15 June 2004
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SUMMARY |
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Key words: Fat, Cadherin, Limb, Growth, Drosophila
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Introduction |
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There is a progressive elaboration of patterning along the PD axis over the
course of wing development (reviewed by
Klein, 2001). During the
second larval instar, interactions among the Epidermal Growth Factor Receptor,
DPP and WG signaling pathways divide the wing disc into a dorsal region, which
will give rise to notum, and a ventral region, from which the wing will arise
(Ng et al., 1996
;
Baonza et al., 2000
;
Wang et al., 2000
;
Cavodeassi et al., 2002
;
Zecca and Struhl, 2002
). An
initial PD subdivision of the wing is then effected by signaling from the AP
and DV compartment boundaries, which promotes the expression of two genes,
scalloped and vestigial, that encode subunits of a
heterodimeric transcription factor (SD-VG) in the center of the wing
(Kim et al., 1995
;
Kim et al., 1996
;
Zecca et al., 1996
;
Neumann and Cohen, 1997
;
Halder et al., 1998
;
Klein and Martinez Arias,
1998
; Simmonds et al.,
1998
). This subdivides the wing into distal cells, which give rise
to the wing blade, and surrounding cells, which give rise to proximal wing and
wing hinge structures (Fig. 1) (Kim et al., 1996
;
Klein and Martinez Arias,
1998
; Azpiazu and Morata,
2000
; Casares and Mann,
2000
; Liu et al.,
2000
). The proximal wing is further subdivided into a series of
molecularly distinct domains (Fig.
1B). Studies of SD-VG function in the wing led to the realization
that the elaboration of this finer pattern depends in part upon signaling from
the distal, SD-VG-expressing cells, to more proximal cells
(Liu et al., 2000
). Thus,
mutation of vg leads to elimination, not only of the wing blade,
where VG is expressed, but also of more proximal tissue
(Williams et al., 1991
;
Williams et al., 1993
;
Klein and Martinez Arias,
1998
; Liu et al.,
2000
). Conversely, ectopic expression of VG in the proximal wing
reorganizes the patterning of surrounding cells
(Liu et al., 2000
;
del Álamo Rodriguez et al.,
2002
; Kolzer et al.,
2003
).
|
In this work, we identify Four-jointed (FJ), Dachsous (DS), Fat and Dachs
as proteins that influence signaling to proximal wing cells to regulate WG and
rn expression. FJ is a type II transmembrane protein, which is
largely restricted to the Golgi (Villano
and Katz, 1995; Brodsky and
Steller, 1996
; Buckles et al.,
2001
; Strutt et al.,
2004
). Null mutations in fj do not cause any obvious
defects in the proximal wing (Villano and
Katz, 1995
; Brodsky and
Steller, 1996
). However, fj plays a role in the
regulation of tissue polarity, yet acts redundantly with some other factor(s)
in this process (Zeidler et al.,
1999
; Zeidler et al.,
2000
; Casal et al.,
2002
). Mutations in fat or ds can also influence
tissue polarity (Adler et al.,
1998
; Casal et al.,
2002
; Rawls et al.,
2002
; Strutt and Strutt,
2002
; Yang et al.,
2002
; Ma et al.,
2003
), and both genes encode large protocadherins
(Mahoney et al., 1991
;
Clark et al., 1995
). Although
the molecular relationships among these proteins are not well understood,
genetic studies suggest that fj and ds act via effects on
fat, and both fj and ds can influence Fat
localization in genetic mosaics (Strutt
and Strutt, 2002
; Yang et al.,
2002
; Ma et al.,
2003
).
Interestingly, alleles of fj, ds and fat, as well as
alleles of another gene, dachs, can result in similar defects in wing
blade and leg growth (Mohr,
1923; Waddington,
1943
). The similar requirements for these genes during both
appendage growth and tissue polarity, together with the expression patterns of
fj and ds in the developing wing, led us to investigate
their requirements for proximal wing development. We find that all four genes
influence the expression of WG in the proximal wing, and genetic experiments
suggest a pathway in which FJ and DS act to modulate the activity of Fat,
which then regulates transcription via a pathway that includes Dachs. Our
observations lend strong support to the hypothesis that FJ, DS and Fat
function as components of an intercellular signal transduction pathway,
implicate Dachs as a key downstream component of this pathway, and identify a
normal role for these genes in proximodistal patterning during
Drosophila wing development.
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Materials and methods |
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Clones of cells ectopically expressing genes of interest (Flip-out) were
generated by combining transgenes that provide expression under UAS control
with transgenes that allow the generation of clones of cells expressing the
Gal4 protein (AyGal4) (Ito et al.,
1997). Gal4-expressing clones were marked using a UAS-GFP
transgene. Flip-out clones were induced at 24-48 and 48-72 hours AEL.
Immunostaining
Imaginal discs from third instar larvae were fixed and stained as
previously described (Liu et al.,
2000), using as primary antibodies: rabbit anti-VG (1:600, S.
Carroll, University of Wisconsin-Madison), mouse anti-WG 4D4 (1:1000,
Developmental Studies Hybridoma Bank), mouse anti-NUB (1:100, S. Cohen,
European Molecular Biology Laboratory), rabbit anti-ß-gal (1:2000, ICN),
Goat anti-ß-gal (1:1000, Biogenesis), mouse anti-ß-gal (1:1000,
Sigma), rabbit anti-MYC (1:100, Santa Cruz), rat anti-MYC (1:1000, Serotec),
rat anti-DS (1:200, M. Simon, Stanford University) and rat anti-Fat (1:100, H.
McNeill, Cancer Research UK). For precise timing, larvae were collected in
intervals after the second to third instar molt, but in some cases ages were
estimated based on the size and morphology of the disc.
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Results |
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|
To further examine this possibility, we analyzed vg fat double
mutants. vg mutant wing discs contain a single ring of WG expression,
which, based on the NUB expression domain, appears to correspond to the outer
WG ring (Fig. 3A)
(Liu et al., 2000). Expression
of WG in the inner ring, which normally overlaps NUB, is either not detected
(8/14 discs), or is reduced to a small central spot (6/14 discs) in
vg mutants (Fig. 3A).
Importantly, in vg fat double mutants, WG expression is always
observed in the center of the disc (7/7 discs), and this expression is
substantially enlarged (Fig.
3B). The observation that mutation of fat can promote WG
expression even in the absence of VG is consistent with the hypothesis that
Fat is normally repressed downstream of a VG-dependent signal.
|
|
|
|
|
Mutation of fj impairs the initiation of WG expression in the proximal wing
The proximal wing appears normal in fj null mutant animals
(Villano and Katz, 1995;
Brodsky and Steller, 1996
).
Thus, if FJ contributes to distal signaling, it must do so redundantly.
Nonetheless, we considered the possibility that some reduction in WG
expression might be detectable in fj mutants. In order to enhance our
ability to detect subtle changes, WG was examined in fj genetic
mosaics. In this situation, regions of the disc composed of wild-type cells
provide an internal control for normal levels of staining. Importantly, at
early to mid third instar, WG expression in the distal ring was reduced in
cells adjacent to fj mutant distal wing cells
(Fig. 8A,B; 10/13 early discs
with clones had detectable alterations in WG expression). WG expression was
never completely eliminated, consistent with notion that FJ contributes to,
but is not absolutely required for, WG expression. The influence of FJ on WG
expression depended on the genotype of distal wing cells rather than proximal
wing cells (Fig. 8A,B),
consistent with the fj expression pattern
(Fig. 5). Intriguingly, WG
expression sometimes (7/32 clone edges) also appeared elevated in mutant cells
immediately adjacent to wild-type cells
(Fig. 8A). The altered
expression of WG indicates that FJ contributes to normal distal signaling, but
is not solely responsible for it.
|
Expression of dachsous during wing development
Studies of tissue polarity suggest a close functional relationship among
fj, fat and ds. ds is expressed preferentially by proximal
wing cells (Clark et al.,
1995), but low levels have been reported in more distal cells
(Strutt and Strutt, 2002
;
Ma et al., 2003
). During third
instar, both DS protein expression and ds transcription, as detected
by a lacZ enhancer trap line, appear graded, with the highest levels
in proximal wing cells and the lowest levels in distal wing cells
(Fig. 5B,D). When the inner
ring of WG expression is first detected, at early third instar, it appears on
the slope of DS expression, with the highest levels of DS more proximal, and
the lowest levels of DS more distal.
dachsous influences WG expression in the proximal wing
Neither ds mutant discs (not shown), nor fj ds double
mutant discs (Fig. 3C), exhibit
obvious changes in WG expression, nor do they display the overgrowths of wing
tissue observed in fat mutants. Nonetheless, clones of cells mutant
for a strong ds allele, dsUA071, can exert a
subtle influence on WG expression. At early third instar, this influence is
most often detected as a slight decrease in WG within ds mutant
cells, and a slight increase in WG in wild-type cells that border the clone
(18/37 early to mid third instar clones revealed this effect)
(Fig. 9A), although in some
cases (8/37) WG expression appeared slightly elevated within mutant cells. At
late third instar a slight increase in WG expression is most often (19/35
clones) observed within ds mutant cells
(Fig. 9B), and a decrease in WG
expression is only rarely (3/35 clones) observed. Similarly, at early to mid
third instar, ectopic expression of DS was often (12/23 cases) associated with
upregulation of WG within DS-expressing cells at the edge of clones
(Fig. 9C), although
occasionally (4/23 cases) WG was upregulated in neighboring cells
(Fig. 9D). At late stages
elevation of WG expression in neighboring cells was observed (12/12 cases).
Although the influence of DS is complex (see Discussion), its ability to
modulate WG expression in the proximal wing is consistent with the suggestion
that it can influence Fat activity. It has been reported previously that Fat
localization is altered by ds mutant clones
(Strutt and Strutt, 2002;
Ma et al., 2003
), and we find
that clones of cells ectopically expressing DS can also influence Fat
localization (Fig. 9F). To
investigate possible interactions between ds and fj, we also
examined clones of cells co-expressing both genes. These are associated with
non-autonomous upregulation of WG at all stages
(Fig. 9E).
|
|
dachs is epistatic to fat
dachs has recently been found to encode an unconventional myosin
(F. Katz, personal communication), and thus is presumably a cytoplasmic
protein. The autonomous influence of dachs on WG expression, together
with its presumed cytoplasmic location, suggested that it might act downstream
of fat. Since mutation of fat and mutation of dachs
have opposing effects on WG, this possibility could be tested genetically. In
d1 fat8 double mutant clones, the influence of
dachs on WG expression is epistatic, as clones in early third instar
discs exhibit the same reduction in WG expression that is observed in
d1 mutant clones (12/12 clones)
(Fig. 10D). At later stages,
WG expression partially recovers (18 clones), but at no time do the clones
exhibit significant ectopic WG expression
(Fig. 10E). Interestingly, the
dachs phenotype is also epistatic for the growth effects of
fat, as the overgrowth phenotype of fat mutant discs is
partially suppressed in animals that are also heterozygous for
d1 (data not shown), and completely suppressed in animals
that are homozygous for d1
(Fig. 4F).
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Discussion |
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Regulation of Fat activity
The common feature of all of our manipulations of FJ and DS expression is
that WG expression, and by inference, Fat activity, can be altered when cells
with different levels of FJ or DS are juxtaposed. In the case of FJ, its
normal expression pattern, mutant clones and ectopic expression clones are all
consistent with the interpretation that juxtaposition of cells with different
levels of FJ is associated with inhibition of Fat in the cells with less FJ
and activation of Fat in the cells with more FJ
(Fig. 11A). The influence of
DS, however, is more variable. Studies of tissue polarity in the eye suggested
that DS inhibits Fat activity in DS-expressing cells, and/or promotes Fat
activity in neighboring cells (Yang et
al., 2002). The predominant effect of DS during early wing
development is consistent with this, but its effects in late discs are not.
Studies of tissue polarity in the abdomen suggest that the DS gradient might
be interpreted differently by anterior versus posterior cells
(Casal et al., 2002
), and it is
possible that a similar phenomena causes the effects of DS to vary during wing
development.
The influence of ds mutation on gene expression and growth in the
wing is much weaker than that of fat. It has been suggested that FJ
might influence Fat via effects on DS
(Yang et al., 2002), and
fj mutant clones have been observed to influence DS protein staining
(Strutt and Strutt, 2002
;
Ma et al., 2003
). Our
observations are consistent with the inference that both DS and FJ can
regulate Fat activity, but they do not directly address the question of
whether FJ acts through DS. They do, however, indicate that even the combined
effects of FJ and DS cannot account for FAT regulation, and, assuming that the
strongest available alleles are null, other regulators of Fat activity must
exist. It is presumably because of the counteracting influence of these other
regulators that alterations in FJ and DS expression have relatively weak
effects. In addition, according to the hypothesis that Fat activity is
influenced by relative rather than absolute levels of its regulators, the
effects of FJ or DS could be expected to vary depending upon their temporal
and spatial profiles of expression, as well as on the precise shape and
location of clones.
Downstream signaling
Our observations, together with those of Fanto et al.
(Fanto et al., 2003), imply
the existence of at least two intracellular branches of the Fat signaling
pathway (Fig. 11A). One branch
involves the transcriptional repressor Grunge, influences tissue polarity,
certain aspects of cell affinity, and fj expression, but does not
influence growth or WG expression. An alternative branch does not require
Grunge, but does require Dachs. Dachs is implicated as a downstream component
of the Fat pathway, based on its cell autonomous influence on Fat-dependent
processes, and by genetic epistasis. The determination that it encodes an
unconventional myosin (F. Katz, personal communication), and hence presumably
a cytoplasmic protein, is consistent with this possibility. It also suggests
that it does not itself function as a transcription factor, and hence implies
the existence of other components of this branch of the Fat pathway. This
Grunge-independent branch influences WG expression in the proximal wing and
imaginal disc growth. However, further studies will be required to determine
whether Dachs functions solely in Grunge-independent Fat signaling, or whether
instead Dachs is required for all Fat signaling.
Distal-to-proximal signaling in the wing
The observations that fj expression is regulated by SD-VG, and
that fj is both necessary and sufficient to modulate the distal ring
of WG expression in the proximal wing, suggest that FJ influences the activity
of a distal signal, which then acts to influence Fat activity
(Fig. 11B). However, the
relatively weak effects of fj indicate that other factors must also
contribute to distal signaling (X in Fig.
11B), just as fj functions redundantly with other factors
to influence tissue polarity. As DS expression is downregulated in a domain
that is broader than the VG expression domain, a direct influence of VG on the
DS gradient is unlikely, and the essentially normal appearance of WG
expression in the proximal wing in fj ds double mutants implies that
DS is not a good candidate for Signal X. Rather, we suggest that DS acts in
parallel to signaling from VG-expressing cells to modulate Fat activity. This
VG-independent effect would account for the remnant of the distal ring that
sometimes appears in vg null mutants
(Fig. 3A)
(Liu et al., 2000).
Importantly though, the observation that the phenotypes of hypomorphic
dachs mutant clones on WG expression are more severe than fj
and ds suggests that the hypothesized additional factors also act via
the Fat pathway. We also note that the limitation of WG expression to the
proximal wing even in fat mutant clones implies that wg
expression both requires NUB, and is actively repressed by distally-expressed
genes (Fig. 11B).
The recovery of normal WG expression by later stages in both fj
and dachs mutant clones implies that the maintenance of WG occurs by
a distinct mechanism. Prior studies have identified a positive-feedback loop
between WG and HTH that is required to maintain their expression
(Azpiazu and Morata, 2000;
Casares and Mann, 2000
;
del Álamo Rodriguez et al.,
2002
). We suggest that once this feedback loop is initiated, Fat
signaling is no longer required for WG expression. Moreover, the recovery of
normal levels of WG at late stages suggests that this positive-feedback loop
can amplify reduced levels of WG to near normal levels.
The distinct consequences of VG expression and FJ expression in clones in
the proximal wing suggest that another signal or signals, which are
qualitatively distinct from the FJ-dependent signal, is also released from
VG-expressing cells. When VG is ectopically expressed, WG is often induced in
a ring of expression that completely encircles it
(Liu et al., 2000). However,
this is not the case for FJ-expressing clones. Both VG- and FJ-expressing
clones can activate rn and wg only within NUB-expressing
cells, but VG expression can result in non-autonomous expansion of the NUB
domain, and this expansion presumably facilitates the expression of WG by
surrounding cells (Liu et al.,
2000
; del Álamo
Rodriguez et al., 2002
;
Baena-Lopez and Garcia-Bellido,
2003
). Another striking difference between VG- and FJ-expressing
clones is that in the case of ectopic FJ, enhanced WG expression is only in
adjacent cells. By contrast, in the case of VG, WG expression initiates in
neighboring cells, but often moves several cells away as the disc grows,
resulting in a gap between VG and WG expression. This gap suggests that a
repressor of WG expression becomes expressed there, and recent studies have
identified Defective proventriculus (DVE) as such a repressor
(Kolzer et al., 2003
).
Growth regulation by the Fat signaling pathway
In strong fat mutants, the wing discs become enlarged and have
extra folds and outgrowths in the proximal wing
(Bryant et al., 1988;
Garoia et al., 2000
). The
disproportionate overgrowth of the proximal wing is due to upregulation of WG
in this region, as demonstrated by its suppression by
wgspd-fg (Fig.
4). At the same time, clones of cells mutant for fat
overgrow in other imaginal cells, and fat wgspd-fg discs
are still enlarged compared with wild-type discs. Thus, Fat appears to act
both by regulating the expression of other signaling pathways (e.g. WG), and
via its own, novel growth pathway. The identification of additional components
of this pathway will offer new approaches for investigating its profound
influence on disc growth.
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ACKNOWLEDGMENTS |
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