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doi: 10.1242/10.1242/dev.00379
1 Department of Biology, Tokyo Metropolitan University, Hachioji-shi, Tokyo
192-0397, Japan
2 Department of Molecular and Cellular Biology, and Arizona Cancer Center,
University of Arizona, Tucson, AZ 85724, USA
Present address: Institute for Molecular Science of Medicine, Aichi Medical
University, Nagakute, Aichi 480-1195, Japan
Author for correspondence (e-mail:
hnakato{at}azcc.arizona.edu)
Accepted 8 January 2003
 |
SUMMARY |
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 TOP SUMMARY INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key words: dally, dpp, Morphogen gradient, Heparan sulfate proteoglycan, Drosophila
|
INTRODUCTION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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;
Nellen et al., 1996).
Recently, two molecular tools have been developed to monitor the Dpp gradient
formation. First, a biologically active GFP-tagged Dpp (Dpp-GFP) was used to
directly visualize the Dpp gradient in the developing wing
(Fig. 1A)
(Entchev et al., 2000;
Teleman and Cohen, 2000).
Studies using Dpp-GFP successfully demonstrated that Dpp forms a long-range
gradient throughout the wing pouch. Dpp-GFP moves quickly through the disc and
is rapidly turned over. Second, an antibody that specifically recognizes the
phosphorylated form of Mothers against Dpp (pMad) can be used to monitor the
Dpp morphogen activity gradient by following the phosphorylation of Mad, a
downstream transducer of the Dpp pathway
(Fig. 1B)
(Persson et al., 1998;
Tanimoto et al., 2000).
Generally, pMad levels are high at the central region of the wing disc and
gradually decline toward the anterior and posterior distal cells. However,
within the central region, pMad levels are lower at the A/P border cells owing
to the reduced expression of thickveins (tkv), which encodes
the type I receptor for Dpp. Although the ligand and activity gradients now
can be visualized by using the tools mentioned above, the molecular basis for
the Dpp gradient formation is not yet completely understood.
|
). In
addition, tkv expression is strongly repressed by Hh signaling at the
A/P border cells, which results in a reduction of pMad staining in this
region. The basal level of tkv expression is higher in the P
compartment than in the A compartment and is maintained by the activity of the
P cell-specific selector gene, engrailed (en)
(Funakoshi et al., 2001;
Tanimoto et al., 2000). As
higher levels of Tkv limit the movement of Dpp, Dpp does not spread as far in
the P compartment, resulting in a steeper Dpp morphogen gradient.
Overexpression of tkv was also shown to retard the movement of Dpp
(Lecuit and Cohen, 1998;
Tanimoto et al., 2000). Thus,
Dpp gradient formation is in part controlled by the regulated expression of
the tkv gene.
Several lines of evidence have suggested that heparan sulfate proteoglycans
(HSPGs) are involved in distribution of morphogens. tout velu
(ttv), a Drosophila homolog of the mammalian EXT tumor
suppressor gene family, encodes a heparan sulfate co-polymerase
(Bellaiche et al., 1998;
The et al., 1999;
Toyoda et al., 2000).
Mutations in ttv disrupt the movement of Hh from its site of
production. Thus, ttv-dependent synthesis of HSPG is required for
normal distribution of Hh between cells. Similarly, Notum (Wingful) was
recently reported to be required for gradient formation of the Wg morphogen
(Gerlitz and Basler, 2002;
Giraldez et al., 2002). This
gene encodes a protein with homology to pectin acetyltransferases and is
proposed to affect Wg distribution by modulating the structures of the heparan
sulfate moiety of HSPGs. Recently, a novel membrane exovesicle structure,
argosome, was identified and proposed to be involved in morphogen movements
(Greco et al., 2001). The
transportation of argosomes across cells and the localization of Wg protein in
this structure suggests a possible role for argosomes in Wg distribution.
Interestingly, when discs were treated with heparitinases, enzymes that digest
heparan sulfate, Wg failed to accumulate properly in argosomes, although
argosome distribution was not affected. Greco et al. proposed from this
observation that interaction of Wg with HSPGs is required for the
incorporation of Wg into argosomes (Greco
et al., 2001). These findings collectively point to the
possibility that HSPGs are involved in controlling the distributions and
activities of morphogens during tissue patterning.
One of the Drosophila proteoglycan genes that has been shown to
affect growth factor signaling in tissue patterning is division abnormally
delayed (dally) (Nakato et
al., 1995). dally encodes the core protein for glypican,
a family of HSPGs that are linked to the cell membrane through a GPI anchor
(Tsuda et al., 1999).
dally affects signaling mediated by two known HS-binding growth
factors in Drosophila: Dpp and Wg. Modulation of dally gene
dosage dramatically alters the expression of Dpp target genes, as well as the
patterning activity of Dpp in multiple imaginal tissues
(Fujise et al., 2001;
Jackson et al., 1997). In the
embryonic epidermis, dally modulates patterning directed by Wg
(Lin and Perrimon, 1999;
Tsuda et al., 1999). These
findings are consistent with a model in which HSPGs enhance the activity of
growth factors on the cell surface by promoting the assembly and/or increasing
the stability of signaling complexes. In this study, we focused on the
function of dally in Dpp signaling during wing development. We found
that elevated levels of dally increase the sensitivity of cells to
Dpp, and that alterations in levels of dally affect formation of both
Dpp ligand and activity gradients. In addition, we found that the same
regulatory networks control expression of dally and tkv.
These findings suggest that the regulated expression and function of Dally are
essential components for Dpp morphogen gradient formation.
|
MATERIALS AND METHODS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
;
Nakato et al., 1995) and
tkvP906 (Tanimoto et
al., 2000) were used to follow the expression patterns of
dally and tkv, respectively. The mutations and transgenic
animals used were as follows: dallygem and
dallyDP-527, hypomorphic alleles of
dally (Nakato et al.,
1995); Df enE, an embryonic lethal allele of
en (Tabata et al.,
1995); tkva12
(Nellen et al., 1994;
Nellen et al., 1996) and
tkv6 (Singer et al.,
1997), a null and hypomorphic allele of tkv,
respectively; UAS-dally (Tsuda et
al., 1999); UAS-hhCD2, a membrane-tethered form of Hh,
the signaling fragment of Hh fused to the rat CD2 gene
(Strigini and Cohen, 1997);
UAS-tkvQ253D, a constitutively active form of tkv
(Nellen et al., 1996;
Wieser et al., 1995);
Act5C>y+>GAL4, a FLP-OUT cassette to misexpress the
gene downstream of UAS (Ito et al.,
1997); UAS-Dpp-GFP, a biologically active form of Dpp
tagged with GFP (Teleman and Cohen,
2000); and dpp-GAL4
(Morimura et al., 1996).
Immunostaining
Immunostaining was performed as previously described
(Fujise et al., 2001) using
rabbit anti-ß-galactosidase (1:500, Cappel), rabbit anti-pMad [1:1000, a
generous gift from T. Tabata and P. ten Dijke
(Persson et al., 1998;
Tanimoto et al., 2000)] and
rat anti-Tkv [1:250, a generous gift from S. Cohen
(Teleman and Cohen, 2000)].
The intensity profiles of pMad staining were generated by NIH Image using the
plot function. The primary antibodies were detected with Alexa Fluor 568- or
Alexa Fluor 488-conjugated secondary antibodies (Funakoshi).
Ectopic expression
Clones of cells that ectopically express hhCD2,
tkvQ253D and dally were induced by the GAL4/UAS
system using a FLP-OUT cassette (Ito et
al., 1997; Struhl and Basler,
1993). The genotypes of the flies used were:
Mosaic analyses
Homozygous mutant clones were induced by FLP-mediated mitotic recombination
(Golic, 1991;
Xu and Rubin, 1993). Larvae
were heat shocked at 24-48 hours after egg-laying at 37°C for 10-60
minutes to induce recombination. Discs were dissected and analyzed 48-96 hours
after the induction. The genotypes of larvae we used to examine the effect of
tkv mutations on dally::lacZ expression were: Ubi-nlsGFP
FRT40/tkva12 FRT40; dallyP2/FLP3 Sb
MKRS and Ubi-nlsGFP FRT40/tkv6 FRT40;
dallyP2/FLP3 Sb MKRS. To induce en
mutant clones, we used discs from y w hsp70-flp/+;
FRT42D y+ Df enE/FRT42D y+
Ubi-GFP; dallyP2/+ larvae.
Expression and detection of Dpp-GFP
To monitor the Dpp-GFP distribution, we dissected wing discs of
dppd12/+; UAS-dpp-GFP/dpp-GAL4 larvae. Distribution of
Dpp-GFP in dally mutants was observed using discs from
dppd12/+; dpp-GAL4 dallygem/UAS-dpp-GFP
dallygem larvae. The effect of dally overexpression
in A/P border cells on Dpp-GFP distribution was analyzed using discs from
dppd12/+; UAS-dpp-GFP UAS-dally/dpp-GAL4 larvae. In
previous studies (Entchev et al.,
2000; Teleman and Cohen,
2000), Dpp-GFP was expressed in dpp homozygous animals
(dppd8/dppd12 or
dppd12/dppd16). However, because animals
homozygous for both dpp and dally rarely survive to the
third instar, we expressed Dpp-GFP in a dpp heterozygous background
(dppd12/+). After a brief fixation (10 minutes) of discs
with 4% formaldehyde, signals for Dpp-GFP were imaged using confocal
microscopy (LSM410, Carl Zeiss). Average intensity profiles for different
genotypes were generated using NIH Image.
|
RESULTS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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;
Tanimoto et al., 2000). The
activities of both hh and en genes are mediated by a
putative transcription factor, Mtv. Second, tkv levels are
downregulated by Dpp signaling (Lecuit and
Cohen, 1998). By this mechanism, tkv expression is
maintained at low levels in the center of the disc and at higher levels toward
the anterior and posterior edges. The correlation between expression patterns
of dally and tkv prompted us to analyze the dally
function in Dpp signaling in this tissue. As a first step toward this, we
analyzed the regulatory pathways controlling dally expression and
compared them with those controlling tkv expression.
dally expression is regulated by Hh and En
In a previous study, we showed that Hh signaling induces dally
expression at the A/P border cells (Fujise
et al., 2001). dally expression was absent in the
smoothened (smo) mutant clones generated in the A
compartment, where the Hh signaling is blocked
(Alcedo et al., 1996),
indicating that Hh signaling is required for activation of dally at
the A/P border cells. To further determine whether Hh signaling is sufficient
for the induction of dally, we examined clones that ectopically
express hhCD2, which encodes a membrane-tethered form of Hh
(Strigini and Cohen, 1997),
using the FLP-OUT system. In the A compartment, dally expression
levels were increased in hhCD2-expressing cells and in cells
immediately adjacent to them (Fig.
2A-C). This result shows that Hh expression is sufficient to
induce dally expression in the A compartment. To determine if
dally expression is controlled by en, which upregulates
tkv expression, we induced clones of en-mutant cells using
the FLP-FRT mosaic analysis system. Within en-mutant clones in the P
compartment, dally levels were dramatically increased
(Fig. 2D-F), which indicates
that dally expression is negatively regulated by en.
|
). In resultant mosaic discs with wild-type and
tkv-heterozygous cells, dally expression was decreased cell
autonomously in wild-type (+/+) clones at the AP border
(Fig. 3A-C) and peripheral to
the border (Fig. 3D-F). To
further confirm this result, we also examined the effect of
tkv-hypomorphic clones (tkv6/tkv6) on
dally expression. In such clones, where tkv activity is
partially compromised, the levels of dally expression were elevated
(Fig. 3G-I). In the notum
region of the wing disc, we could generate tkv-null clones
(tkva12/tkva12) in which a substantial increase
of dally expression was observed
(Fig. 3J-L). Finally, we tested
the effect of increased Dpp signaling on dally expression by using
the FLP-OUT method to induce clones of cells that express
tkvQ253D, a constitutively active form of tkv, in
the wing pouch. We found that the level of dally::lacZ expression was
autonomously reduced in the tkvQ253D-expressing clones
(Fig. 3M-O). All of these
results consistently indicate that dally expression in the wing disc
is negatively regulated by Dpp signaling, as has been shown for tkv
(Lecuit and Cohen, 1998).
Thus, dally and tkv are regulated by the same set of
molecular pathways: Hh, En and Dpp signaling.
|
), the function of Dally in this signaling pathway during wing
development remains unclear. To investigate whether dally indeed
affects Dpp signaling activity in the developing wing, we examined the effect
of dally misexpression on pMad levels. We found that the pMad signal
was significantly elevated in dally-overexpressing clones induced by
the FLP-OUT system (Fig. 4).
From the observation of 38 clones, this effect of dally+
expression on pMad levels was found to be strictly cell autonomous. This is
consistent with the idea that Dally serves as a co-receptor for Dpp, which
facilitates the assembly of a signaling complex on the cell surface. Given
that Dpp is an unstable molecule with a short half-life
(Teleman and Cohen, 2000), it
is also likely that Dally stabilizes Dpp or the Dpp/receptor complex by
protecting them from extracellular degrading enzymes, or by reducing the rate
at which the internalized signaling complexes are delivered to lysosomes.
Increased pMad staining was observed also in several clones induced at the
hinge region (Fig. 4D-F).
However, in some clones located in the peripheral wing pouch, no increase of
pMad staining was seen (Fig.
4G-I). As Dpp levels are low and the levels of endogenous
dally expression are already high in these regions, the elevated
levels of Dally in this experiment might not be sufficient to induce pMad
accumulation. Thus, dally positively controls Dpp signaling in a cell
autonomous fashion, and the sensitivity of cells to dally
misexpression is different depending on the position of the misexpressing
cells in the wing pouch.
|
|
We noticed that the pMad pattern seen at the dally mutants is
similar to the abnormality observed in discs overexpressing tkv, in
which the elevated levels of Tkv retard the distribution of Dpp protein (data
not shown) (Lecuit and Cohen,
1998; Tanimoto et al.,
2000). This similarity between dally mutants and
tkv-overexpressing discs raises the possibility that dally
normally downregulates tkv expression. In this scenario,
dally mutations would induce high levels of tkv expression,
resulting in abnormal distribution of pMad signals. To determine if this is
the case, we analyzed tkv expression in the same
dally-mutant backgrounds that had been used for the analysis of the
pMad distribution (dallygem/dallygem and
dallygem/dallyDP-527). We
found that levels and expression patterns of tkv::lacZ
(Fig. 6A,B) and Tkv protein
(Fig. 6C,D) in dally
mutants were indistinguishable from those in wild-type discs. This result
indicates that Dally regulates Dpp activity gradient formation via a mechanism
that is independent of tkv expression.
|
;
Teleman and Cohen, 2000).
Dpp-GFP migrates throughout the wing pouch region, forming a shallow but
evident gradient. However, in dally-mutant discs, we could not detect
an evident gradient of Dpp distribution in the receiving cells
(Fig. 7B-D). In general, mutant
discs showed a lower level of cell surface signals, suggesting reduced
stability of Dpp.
|
|
DISCUSSION |
|---|
|
TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
;
Jackson et al., 1997;
Paine-Saunders et al., 2002;
Paine-Saunders et al., 2000).
The present study demonstrates that dally controls shape of both the
ligand and the activity gradients of Dpp in the developing wing. How does
dally contribute to the Dpp gradient formation? In vitro analyses
using mammalian tissue culture cells have established that HSPGs can increase
FGF signaling by stabilizing FGF/FGF receptor complexes
(Sperinde and Nugent, 1998;
Sperinde and Nugent, 2000).
Several lines of evidence indicated that the dosage of HSPGs is an important
factor for FGF signaling. For example, sodium chlorate treatment, which
inhibits the sulfation of heparan sulfate, reduces the biological response of
cells to FGF; the response can be restored by an exogenous supplement of
heparin. However, restoration is seen only at an optimal concentration of
heparin; excess heparin competes for FGF with signaling complex, resulting in
a reduction of signaling (Krufka et al.,
1996). In the Drosophila wing, ectopic expression of
Dally-like, another glypican related to Dally, leads to a massive accumulation
of extracellular Wg protein and compromises Wg signal transduction, suggesting
that the glypicans can affect ligand stability and distribution
(Baeg et al., 2001).
On the basis of these previous studies as well as our data, Dally would
appear to have both positive and negative roles on Dpp signaling
(Fig. 8A). In its positive
role, Dally serves as a co-receptor for Dpp, stabilizing Dpp protein and
enhancing signaling. Conversely, given that Dpp is a heparin-binding protein
(Groppe et al., 1998), Dally
may bind Dpp through its heparan sulfate chains and reduce the amount of free
Dpp ligands. Thus, Dally affects the Dpp gradient at two distinct steps:
signal transduction (autonomous effect) and ligand distribution
(non-autonomous effect). We propose a model in which alterations in the shapes
of the Dpp ligand and the activity gradients caused by dally
mutations and dally overexpression are interpreted as sum of these
plus and minus effects of Dally function. In this model, Dally normally
sequesters Dpp protein to some extent in A/P border cells, where
dally levels are very high. Therefore, reduced levels of Dally in
mutant discs may result in the release of Dpp ligand and, consequently, higher
levels of signaling activity in the central region. Therefore, dally
mutations may severely reduce the stability of Dpp protein as well as its
signaling activity in the receiving cells. When dally is
overexpressed in A/P border cells, Dpp is trapped by binding to excess Dally
and fails to distribute properly.
|
).
However, our results do not rule out the possibility that Dally plays a more
active role in facilitating Dpp diffusion or `carries' Dpp protein. For
example, it is possible that Dally is required for the Dpp movement through
the transcytosis pathway (Entchev et al.,
2000; Gonzalez-Gaitan and
Jackle, 1999) or other transport systems, such as cytonemes
(Ramirez-Weber and Kornberg,
1999) and argosomes (Greco et
al., 2001).
Regulated expression of receptor and co-receptor for stable morphogen
gradient
We also showed that dally expression is regulated by the same set
of signaling pathways that control expression of tkv. Both genes are
regulated by Hh in A/P border cells and by En in the P compartment
(Fig. 1,
Fig. 8B), but the effects of Hh
and En on dally are opposite to those on tkv. In addition,
dally expression is negatively controlled by Dpp signaling. Through
this mechanism, relative levels of dally expression are higher at the
anterior and posterior distal edges. Therefore, dally and
tkv show similar patterns of expression with one exception: the level
of dally expression is high in A/P border cells, where Dpp is
synthesized and secreted, but by contrast, tkv expression levels are
low in this region (Fig. 1,
Fig. 8B). The high levels of
dally in the peripheral regions could sensitize cells to low levels
of Dpp, as has been shown for tkv
(Lecuit and Cohen, 1998).
These regulatory pathways appear to form negative feedback loops, which may
stabilize the shape of the Dpp morphogen gradient. Thus, the regulated
expression and function of Dally are crucial factors in the generation and
maintenance of the Dpp morphogen gradient.
|
ACKNOWLEDGMENTS |
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|
Footnotes |
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