1 Department of Biological Science and Technology, Tokyo University of Science,
2641 Yamazaki, Noda, Chiba 278-8510, Japan
2 School of Biological Sciences, University of Manchester, Stopford Building,
Oxford Road, Manchester M13 9PT, UK
3 Department of Nutrition, School of Medicine, University of Tokushima, 3-18-15
Kuramoto, Tokushima 770-8503, Japan
4 Department of Neuroscience and Immunology, Kumamoto University, Graduate
School of Medical Sciences, Honjo 2-2-1, Kumamoto 860-0811, Japan
5 Department of Physiology, Keio University, School of Medicine, 35
Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
6 Genome and Drug Research Center, Tokyo University of Science, 2641 Yamazaki,
Noda, Chiba 278-8510, Japan
7 PRESTO, JST, 4-1-8 Honcho, Kawaguchi, Saitama, Japan
* Author for correspondence (e-mail: matsuno{at}rs.noda.tus.ac.jp)
Accepted 8 September 2004
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SUMMARY |
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Key words: Notch signaling, Deltex, Endocytic trafficking, Suppressor of Hairless, Drosophila
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Introduction |
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Genetic and molecular studies in Drosophila have led to the
identification of several additional components of the N signaling pathway.
The dx gene encodes a cytoplasmic protein that binds to the
intracellular domain of N and regulates N signaling in a positive manner
(Xu and Artavanis-Tsakonas,
1990; Busseau et al.,
1994
; Diederich et al.,
1994
; Matsuno et al.,
1995
). In the Dx protein, domains involved in distinctive
protein-protein interactions have been identified
(Matsuno et al., 1997
;
Aravind, 2001
;
Matsuno et al., 2002
). In
addition, Dx has a RING-H2 finger motif often found in E3-ubiquitin ligase and
human Dx homologs, the DTX proteins, were recently shown to have
self-ubiquitination activity (Takeyama et
al., 2003
). However, the precise function of Dx in N signaling is
still elusive.
Here, we investigated the function of dx during wing-margin
development. dx, like N (reviewed by
Brook et al., 1996;
Cohen, 1996
;
Irvine and Vogt, 1997
), was
indispensable for this process. In addition, overexpressing Dx led to the
expression of N downstream genes in the wing pouch of the third-instar wing
disc. While the activation of vgBE by the constitutively active
NICD was eliminated in the Su(H) null mutant background,
its activation by Dx was not. This is strong evidence that Dx-dependent N
signaling occurs in a Su(H)-independent manner, as proposed previously
(Ordentlich et al., 1998
;
Ramain et al., 2001
;
Hu et al., 2003
). However,
some of the nucleotide sequences in the Su(H)-binding site of vgBE were also
required for this activation by Dx, leading us to speculate that this region
might also bind to an as-yet-unidentified factor that mediates Dx-dependent
signaling. Dx and N acted synergistically to increase N signaling.
Furthermore, while Su(H) was dispensable for Dx-dependent N signaling, Dx
required N to activate the expression of downstream N target genes. Our
results also showed that the ectopic activation of N signaling associated with
Dx overexpression occurred independent of the Dl/Ser ligands. We found that Dx
promoted the relocation of N from the apical membrane to the late-endosome,
where N was stabilized and co-localized with Dx. Finally, we demonstrated that
blocking N trafficking to the late-endosome prevented the Dx-mediated
activation of N signaling. Together, these results suggest that Dx-dependent
activation of N, which is independent of Su(H), takes place in the
late-endosomal compartments, unlike the N activation in Su(H)-dependent
canonical N signaling, which is thought to occur at the plasma membrane
(reviewed by Ray et al., 1999
;
Mumm and Kopan, 2000
). This is
a rare and perhaps unique example of two distinct signaling pathways
downstream of a single receptor being activated in different membrane-bound
compartments.
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Materials and methods |
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Generation of mosaics
Mitotic clones were generated by Flp-mediated mitotic recombination
(Xu and Rubin, 1993).
Recombination was induced in the second-instar larvae by a 30-minute heat
shock at 37°C. To generate the mutant clones of
Su(H)
47 in wing discs
overexpressing Dx or NICD under the control of dpp-GAL4,
Su(H)
47 FRT40A/CyO,GFP;
dpp-GAL4 vgBE-lacZ/TM6B virgin females were crossed with either
UAS-dx/Y; Ubi-GFP FRT40A/+; hsp70-flp/+ or hsFLP/Y;
Ubi-GFP FRT40A/+; UAS-NICD/+ males, respectively.
To generate the double mutant clones of DlREV10 and
SerRX106 in wing discs overexpressing Dx under the control
of ptc-GAL4, hsFLP/+; ptc-GAL4/+; Ubi-GFP FRT82B/TM6B
virgin females were crossed with UAS-dx/Y; vgBE-lacZ/+;
DlREV10, SerRX106 FRT82B/TM6B males.
Generation of cells overexpressing Dx or NICD
Cells overexpressing Dx or NICD were generated using a technique
that combines the FLP/FRT and UAS/GAL4 systems
(Ito et al., 1997). To analyze
the expression pattern of vgBE or Dl in the clones overexpressing Dx,
UAS-dx;; hsp70-flp virgin females were crossed with either AyGAL4
UAS-GFP/CyO; vgBE-lacZ/TM6B or AyGAL4 UAS-GFP/CyO; Dl-lacZ/TM6B
males, respectively. To analyze the expression pattern of wg in the
clones overexpressing Dx, UAS-dx/Y; wg-lacZ/+; hsp70-flp/+ males were
crossed with AyGAL4 UAS-GFP/CyO virgin females. To analyze the
expression pattern of N in the clones overexpressing Dx or
NICD, N-lacZ/FM6; AyGAL4 UAS-GFP/CyO virgin females were
crossed with either UAS-dx;; hsp70-flp or hsp70-FLP1.22;;
UAS-NICD males, respectively. Clones were induced 24-48 or
60-72 hours after egg laying by a 30-minute heat shock at 37°C, detected
by the expression of GFP, and analyzed in third-instar larvae. To express
N+-GV3 in the eye imaginal discs of GMR-dx flies,
GMR-dx/CyO virgin females were crossed with y w;
hs-N+-GV3 males (Struhl
and Greenwald, 2001
).
Immunohistochemistry and in situ hybridization
The wing imaginal discs dissected from third-instar larvae were stained as
described previously (Matsuno et al.,
2002). The following antibodies were used: rat anti-Dx (1:25)
(Busseau et al., 1994
); mouse
anti-Wg (1:5) (van den Heuvel et al.,
1989
); mouse anti-Cut (1:100)
(Jacobsen et al., 1998
); mouse
(Promega) and rabbit (Cappel) anti-ß-GAL (1:1000); mouse
anti-NICD (1:500) (Fehon et
al., 1991
); mouse anti-GAL4 (1:100) (Santa Cruz Biotechnology);
and anti-Hook (1:500) (Kramer and Phistry,
1996
). FITC- (Jackson Laboratories), Alexa 488- (Molecular
Probes), rhodamine- (Chemicon) and Cy5- (Rockland) conjugated secondary
antibodies were used at a dilution of 1:200. In situ hybridization with GAL4
or wg digoxigenin-labeled RNA probe was performed as described
previously (Gonzalez-Crespo and Levine,
1993
).
Detection of endocytic vesicles
Dissected third-instar larval disc complexes were incubated in 0.1 mg/ml
fluorescein Dextran (3000 MW, anionic, lysine fixable; Molecular Probes) in M3
medium at 25°C for 10 minutes (pulse), then washed five times in ice-cold
M3 medium. After a variable chase period (0-60 minutes), they were fixed as
described previously (Matsuno et al.,
2002). Dextran is taken up by endocytosis and marks progressively
later endocytic compartments as the chase time is increased
(Entchev et al., 2000
). To
visualize endocytic vesicles in the Drosophila cell line S2
overexpressing Dx, UAS-dx-YFP was driven by pWA-GAL4.
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Results |
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|
|
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The Su(H)-independent function of Dx raised the possibility that Dx may not be directly involved in N signaling. Therefore, we examined whether the activity of Dx is dependent on N. Overexpression of Dx under the control of ptc-GAL4 resulted in the ectopic activation of Wg, mostly, but not exclusively, in the ventral compartment (Fig. 3O). However, this preferential activation of Wg was not strictly determined, because in cells overexpressing Dx the wg promoter was activated equally well in the dorsal and ventral compartments (data not shown). This Dx activity was then examined when N was knocked down by RNA interference. An inverted repeat RNA corresponding to N (NIR) was co-expressed with Dx, under the control of ptc-GAL4. Under this condition, N protein was barely detected in the region expressing NIR (data not shown). Co-expression of NIR inhibited the ectopic activation of wg associated with the overexpression of Dx, as well as endogenous wg expression (Fig. 3Q,R). The ectopic activation of vgBE by Dx was also abolished by co-expression with NIR (data not shown). These results indicate that Dx function requires N and suggest that Dx functions upstream of N. In agreement with this, we found that co-expression of Dx and N showed a synergistic effect on the ectopic activation of wg (Fig. 3T-V). Similar synergistic activation was observed using vgBE (data not shown). In contrast, we found that the ectopic activation of vgBE by the overexpression of Dx occurred independently of the Dl/Ser ligands. In clonal cells simultaneously homozygous for both Dl and Ser, Dx overexpression still activated vgBE equally well as in wild-type cells (Fig. 3W-Z).
Dx promotes the relocalization of N from the apical plasma membrane to the intracellular vesicles
Based on the finding that Dx functions upstream of N, we decided to examine
the possibility that Dx might affect the cellular N protein directly. In
epidermal cells, the N protein was localized to the apical lateral adhesion
junction with only a small proportion in the basal intracellular vesicles
(Fig. 4A-L). This distribution
is consistent with previous reports (Fehon
et al., 1991). However, when Dx was overexpressed, N was
considerably depleted from the cell surface
(Fig. 4A). In the basal region
of Dx-expressing cells, vesicular staining of N became more prominent
(Fig. 4B). In the optical
vertical section, the relocalization of N protein from the apical surface to
basal intracellular vesicles was observed in the region overexpressing Dx
(Fig. 4I). The numbers of
N-containing vesicles in the wild-type and Dx-overexpressing cells were
counted to quantify this result. Given the number in each wild-type cell as
100, each Dx overexpressing cell had 269±18 vesicles. In contrast, the
number of Dl-containing vesicles was not altered significantly in the
Dx-overexpressing cells (114±38). Next, we analyzed the nature of these
vesicles. Fluorescent Dextran added extracellularly was internalized in the
vesicles containing N, indicating that these vesicles were of endocytic origin
(Fig. 4M,N). Dx was often but
not always associated with these vesicles
(Fig. 4O). Markers for the
endoplasmic reticulum (ER) and Golgi apparatus did not overlap with these
vesicles (data not shown). It has been reported that mammalian homologs of Dx
are localized to the nucleus in cultured cells
(Yamamoto et al., 2001
;
Hu et al., 2003
). In contrast,
we did not observe the nuclear localization of Drosophila Dx under
any of the conditions tested in vivo or in cultured cells (data not shown). We
also noted that, in the basal region of wild-type cells, the Dl protein was
mostly co-localized with N in intracellular vesicles
(Fig. 4B,D). In contrast, in
Dx-overexpressing cells, the Dl protein was not detected in the vesicles
containing N, but accumulated slightly at the apical surface
(Fig. 4B-D). These results
suggest that Dx selectively affects the relocalization of N to the basal
intracellular vesicles.
|
|
Transportation of N to the late-endosome is required for Dx-mediated activation of the N signal
We next attempted to define the nature of the endocytic vesicles associated
with Dx-mediated signaling. Clathrin-dependent endocytosis involves the
formation of vesicles with a clathrin coat, which is visualized by
clathrin-GFP (Chang et al.,
2002). Most of the vesicles labeled with Clathrin-GFP did not
stain for N, although a small population of clathrin-positive vesicles did
contain it (Fig. 6A-D). The N
protein did not co-localize with Hook (Hk), a marker for early-endosomes
(Fig. 6E-H)
(Kramer and Phistry, 1996
).
However, N and Dx co-localized with Rab7-GFP, a marker for late-endosomes
(approximately 80% of the Rab7-GFP-positive vesicles were also N-positive)
(Fig. 6I-L)
(Entchev et al., 2000
). Dx-YFP
also co-localized with vesicles stained with LysoTracker, a marker for acidic
intracellular vesicles, which are mostly late-endosomes and lysosomes in the
Drosophila S2 cell line (Fig.
6M-O). These results suggest that Dx probably promotes the
accumulation of N in the late-endosomal compartment, where Dx co-localizes
with N.
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Discussion |
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Dx regulates the membrane trafficking of N
Here, we demonstrated that the overexpression of Dx depleted N from the
apical cell surface and increased the number of endocytic vesicles containing
N. Dx extended the half-life of N, although it was not clear whether this was
due to the prolonged half-life of the vesicles or to stabilization of the N
protein itself inside them. N accumulated in the late-endosomal compartment,
which was identified by the Rab7-GFP marker. Several models could explain this
accumulation of N. First, Dx may promote the initiation of endocytic vesicle
formation. However, we think this is unlikely, because we did not observe an
increase in N-containing vesicles at the early stage of hs-N+-GV3
turnover (data not shown). Second, Dx may interfere with membrane-trafficking,
consequently preventing N from becoming degraded, or sustaining the half-life
of vesicles containing N. There is accumulating evidence that the degradation
of many transmembrane receptors, which leads to the downregulation of
signaling, occurs in the lysosome. Thus, we speculate that Dx interferes with
the delivery of N to the lysosome. In dx mutant cells, we observed a
reduced number of N-containing vesicles, which is consistent with our idea
that in wild-type cells, Dx also prevents N from relocating to the lysosomes,
where it would be degraded. In Drosophila, it is known that Scabrous
and Gp150, which localize to the late-endosome, negatively regulate N
signaling; however, whether there is any functional relationship between Dx
and these proteins remains to be studied
(Li et al., 2003). In
addition, Dx may play a role in receptor recycling, another process known to
involve protein sorting to multivesicular bodies (MVBs), given that N at the
apical plasma membrane was significantly depleted by Dx overexpression.
However, the precise functions of Dx in these poorly understood processes
remain to be addressed.
Two distinct N signaling pathways may be activated in different membrane compartments
It is known that receptor-mediated signaling can be upregulated by the
inhibition of receptor degradation by preventing its endosome-to-lysosome
delivery (Entchev et al.,
2000). Although Dx overexpression resulted in the accumulation of
N in the late-endosome, our results suggest that this triggered a signaling
event that was distinct from canonical N signaling, rather than merely
upregulating signaling by increasing the availability of N. Indeed, we found
that the consequence of overexpressing full-length N was very different from
that of overexpressing Dx [figure 5F in Matsuno et al.
(Matsuno et al., 2002
)]. In
this respect, it is notable that two contradictory views have been reported
regarding the intracellular compartments where Presenilin cleaves N in
mammalian cells, although this issue has not been addressed in
Drosophila. One view is that the cleavage of N occurs at the plasma
membrane (Ray et al., 1999
;
Brown et al., 2000
), while
another group showed that Presenilin has a low optimal pH, raising the
possibility that it is active in the acidic endocytic compartments, such as
late-endosomes (Pasternak et al.,
2003
; Gupta-Rossi et al.,
2004
). This discrepancy can be resolved by a hypothesis that two
distinct N signaling pathways are executed in different membrane-bound
compartments. Namely, the Su(H)-dependent canonical pathway and the
Dx-mediated signaling pathway occur at the plasma membrane and the
late-endosome, respectively. However, the biochemical mechanism of N
activation in the late-endosomal compartment is virtually unknown. We also
found that the ectopic activation of N signaling associated with Dx
overexpression does not depend on the Dl/Ser ligands, which has been suggested
before (Ramain et al., 2001
).
However, it was recently reported that F3/Contactin, a novel ligand for
mammalian N, specifically activates Dx-mediated N signaling
(Hu et al., 2003
). Therefore,
Drosophila Dx may need an F3/Contactin ortholog to activate vgBE. It
is possible that the Su(H)-dependent and -independent N pathways are
selectively activated by specific sets of N ligands, such as Dl/Ser and
F3/Contactin.
In Drosophila, the dx wing-margin phenotype is completely
suppressed by mutations of Suppressor of deltex [Su(dx)],
which encodes a HECT domain E3 ubiquitin ligase, and this product binds to the
intracellular domain of N (Fostier et al.,
1998; Cornell et al.,
1999
). Indeed, itch, a mouse homolog of Su(dx), binds to the
intracellular domain of mouse notch-1 through its WW domains and promotes the
ubiquitination of N (Qiu et al.,
2000
). Recently, it was shown that the mono-ubiquitination of
transmembrane proteins facilitates their incorporation into endocytic vesicles
and lysosomal delivery (reviewed by
Katzmann et al., 2002
). Given
that Dx is also an E3 ubiquitin ligase and affects membrane trafficking, a
balance between Dx and Su(dx) activity may be important for controlling the
rate of lysosomal delivery. Studies in progress should increase our
understanding of the trafficking of N protein, which is probably a pivotal
element in both the positive and negative regulation of N signaling.
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ACKNOWLEDGMENTS |
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