1 Department of Biological Chemistry, Johns Hopkins School of Medicine, 725 North Wolfe Street, Baltimore, MD 212052, USA
Author for correspondence (e-mail:
dmontell{at}jhmi.edu)
Accepted 19 May 2005
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SUMMARY |
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Key words: Stat, Cell migration, Border cells, Drosophila
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Introduction |
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The JAK/STAT pathway is activated when an extracellular signal, such as a
cytokine, binds to a receptor that constitutively associates with a JAK (Levy,
2002). Ligand binding activates JAK, leading to its autophosphorylation, as
well as to phosphorylation of tyrosine residues on the receptor, which serve
as docking sites for STAT to bind via its SH2 domain. STAT is then
phosphorylated by JAK, dimerizes, and translocates into the nucleus where it
activates the transcription of target genes. This pathway can be regulated at
various steps. For example, SOCS proteins are thought to inhibit STAT function
by blocking its activation or by promoting JAK protein degradation
(Alexander, 2002), whereas PIAS
proteins inhibit STAT activity in the nucleus (Kotaja, 2002).
JAK/STAT signaling is well known to promote cell proliferation, survival
and cell fate determination (Levy, 2002). In addition, recent studies have
identified a requirement for STAT in cell migration in vivo. STAT3 knockout
mice are embryonic lethal, dying during gastrulation
(Takeda et al., 1997).
Conditional knockout of STAT3 in keratinocytes inhibits wound healing in the
mouse and keratinocyte migration in a monolayer-wounding assay
(Sano et al., 1999
). In
zebrafish, STAT3 is essential for the migration of sheets of cells during
gastrulation, independent of an effect upon cell fate
(Yamashita et al., 2002
).
Recently, STAT has been shown to be essential for the migration of primordial
germ cells in Drosophila (Li et
al., 2003
).
Border cell migration in the Drosophila ovary is an excellent
model for the study of developmentally regulated cell motility. The
Drosophila ovary is composed of egg chambers, each of which contains
16 germline cells and about 900 somatic cells, called follicle cells
(Fig. 1A). Early in oogenesis a
pair of special follicle cells forms at each end of the egg chamber, the
so-called polar cells. As oogenesis proceeds the follicle cells differentiate
into several sub-types, including stalk cells, which separate adjacent egg
chambers, squamous follicle cells, which cover the nurse cells, outer follicle
cells, which cover the oocyte, and the border cells. At the beginning of stage
nine of oogenesis, the border cell cluster forms when the anterior polar cells
recruit a group of four to eight cells from the adjacent follicular epithelium
(Grammont and Irvine, 2002;
Montell, 2003
;
Xi et al., 2003
). The cells
delaminate and migrate as a cluster surrounding the two central anterior polar
cells. Over a 6-hour period, the border cell cluster migrates to the oocyte
and eventually contributes to the formation of a structure called the
micropyle, which is the site of sperm entry and is required for fertilization
to occur.
JAK/STAT signaling is essential for border cell migration
(Beccari et al., 2002;
Ghiglione et al., 2002
;
Silver and Montell, 2001
;
Xi et al., 2003
). The
best-characterized components of the JAK/STAT signaling pathway in
Drosophila are a secreted ligand called UPD, its receptor, called
Domeless (DOME), a JAK, referred to as HOP, and STAT92E (STAT). There also
appear to be additional upd-like and domeless-like genes in
the Drosophila genome (Hombria
and Brown, 2002
). UPD is expressed and required in the polar cells
to recruit the surrounding cells to form the border cell cluster
(Silver and Montell, 2001
).
Loss of either hop or stat in the border cells inhibits
their recruitment into the cluster and their subsequent migration.
Furthermore, activation of the JAK/STAT pathway is sufficient to induce
additional follicle cells to become invasive
(Silver and Montell, 2001
). In
the current study, we asked whether STAT is required continuously during
border cell migration, after the fate of the cells has been determined. We
present evidence that the STAT protein accumulates in response to activation
of the JAK/STAT pathway and is highly enriched in the migrating border cells
throughout the migration. Using a temperature-sensitive (ts) allele, we show
that we can separate the requirement for stat in migration from the
requirement in cell recruitment and specification. We also present evidence
that activity of this pathway is regulated by positive feedback, by the
presence of inhibitors and by endocytosis. Together, our results demonstrate a
continuous requirement for STAT signaling during border cell migration and
indicate the importance of regulating the level of this activity.
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Materials and methods |
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To generate stat mosaic mutant follicle cells,
stat92E397, FRT82B flies were crossed to hs-FLP;
ubiquitin-nuclear-GFP, FRT82B. Clones marked by loss of GFP were induced as
described (Silver and Montell,
2001). Flies of the appropriate genotype were heat shocked for one
hour three times a day, for 2-3 consecutive days, and were dissected seven
days later.
The `FLP-out' GAL4 (AyGAL4) system was used to express UAS-upd and UAS-upd(TM). Female flies were heat shocked at 37°C for 1 hour and incubated for 1-2 days at 25°C. Clones were detected by the expression of UAS-lacZ using an anti-ß-galactosidase antibody.
Immunohistochemistry
Ovaries were dissected in Grace's medium containing 10% fetal calf serum.
Immunohistochemical staining was performed as described
(Silver and Montell, 2001).
The following antibodies were used: affinity-purified rabbit anti-STAT at a
dilution of 1:1000 (a generous gift from Stephen Hou); mouse anti-Fasciclin
III at 1:20 (Developmental Studies Hybridoma Bank); rabbit anti-Domeless at
1:200 (S. Noselli); rat anti-DE-cadherin at 1:20 (DSHB); rabbit anti-GFP at
1:2000 (Promega); mouse anti-singed at 1:1 (DSHB); rabbit
anti-ß-galactosidase at 1:1000 (Promega); and mouse anti-armadillo at
1:100 (DSHB). Staining with DAPI and phalloidin was performed as described
(Silver and Montell,
2001
).
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Results |
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We found STAT to be expressed throughout oogenesis in a highly specific and
dynamic pattern. Early in oogenesis, STAT was expressed in the germarium, at
the border between regions IIA and IIB
(Fig. 1B). This region is
thought to contain the somatic stem cells that give rise to all follicle
cells, including the border cells
(Margolis and Spradling,
1995). STAT protein was not detected in the germline. Although
STAT appeared to be mostly cytoplasmic in the anterior and posterior polar
cells, it was enriched in nuclei in the stalk cells at early stages
(Fig. 1C), consistent with the
known function of STAT in specifying stalk cell fate
(Grammont and Irvine, 2002
;
McGregor et al., 2002
; Xi,
2003).
At stage eight, when STAT localization was primarily cytoplasmic in most
follicle cell types, it was highly enriched in the nuclei of about 10 anterior
follicle cells, most of which become incorporated into the border cell cluster
(Fig. 1D). STAT nuclear
localization was maintained in the border cells throughout their migration
(Fig. 1E-H). Because activated
STAT translocates from the cytoplasm into the nucleus, STAT localization in
the nucleus is a strong indicator of the cells with active JAK/STAT signaling.
STAT was also expressed, although primarily in the cytoplasm, in the squamous
follicle cells covering the nurse cells as well as in those in contact with
the oocyte (Fig. 1D). During
stage nine, STAT was also enriched in the nuclei of posterior follicle cells
(Fig. 1E,F,
Fig. 2C), consistent with the
previously described role for JAK/STAT in promoting posterior follicle cell
fates (McGregor et al.,
2002).
|
STAT activity is required throughout border cell migration
Because STAT was highly enriched in the nuclei of border cells throughout
their migration, we postulated that STAT is required not only to specify
border cells and initiate their migration, but also during their migration. To
address this theory, we investigated whether there were stat mutants
in which border cell migration defects occurred in the absence of effects on
cell number or cell fate. In a hypomorphic allelic combination of
stat397/statep3391, STAT protein staining was
barely detectable in border cells (data not shown). In such egg chambers,
border cell migration was dramatically reduced (69% of egg chambers exhibited
a border cell migration defect, n=81), yet the average number of
cells in the cluster was similar to in wild type (5.6 versus 6, respectively).
Consistent with this finding, egg chambers with mosaic clones of
stat, analyzed 3-5 days after clone induction, exhibit border cell
migration defects but do not show altered border cell number or expression of
downstream targets such as SLBO (Beccari et
al., 2002; Silver and Montell,
2001
).
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Consistent with a requirement in cluster organization, when JAK/STAT
signaling was reduced by overexpression of a dominant-negative form of
dome lacking the cytoplasmic domain, border cells migrated slower
than wild-type cells, and frequently as single cells
(Fig. 7D-F). This is consistent
with the finding that in dome mosaic egg chambers, border cells often
fail to migrate in a cluster (Ghiglione et
al., 2002). Taken together, these results support the idea that
signaling through the JAK/STAT pathway is responsible for the organization of
the border cell cluster.
JAK/STAT signaling is regulated by endocytosis
Border cells appear to be sensitive to levels of JAK/STAT signaling, as
both gain-of-function and loss-of-function mutants of the JAK/STAT pathway
cause migration defects. Receptor-mediated endocytosis is known to decrease
signaling through the EGF receptor, but can increase signaling of RTK, and
increase DPP signaling (Jekely and Rorth,
2003; Zhu and Scott,
2004
). We tested the effects of inhibiting endocytosis on
signaling through the JAK/STAT pathway and on border cell migration. We
overexpressed, specifically in border cells, a dominant-negative form of
shibire, which is the fly homolog of Dynamin, a GTPase required for
endocytosis (Ramaswami et al.,
1993
). This treatment induced a border cell migration defect in
95% (n>50) of egg chambers
(Fig. 8A,B).
We then investigated whether the expression of JAK/STAT components was
affected in these mutants. In wild-type egg chambers, the receptor Domeless is
expressed at a low level in all follicle cells, including border cells
(Ghiglione et al., 2002)
(Fig. 8C). By contrast, in egg
chambers in which dominant-negative shibire was expressed
specifically in border cells and posterior follicle cells, there was an
increase in the level of Domeless protein at the cell surface
(Fig. 8E). This was also
apparent when using a UAS-domeless-GFP fusion protein
(Fig. 8D,F). Whereas in
wild-type follicle cells Dome-GFP was concentrated in intracellular puncta, in
follicle cells expressing dominant-negative dynamin, Dome-GFP was concentrated
at the cell surface. This effect was specific because the distribution of
E-Cadherin, another cell surface receptor, appeared to be normal in cells
expressing dominant-negative dynamin (Fig.
8G,H). This result indicates that the level of Domeless protein at
the cell surface is normally dynamically regulated by endocytosis.
Our finding that STAT protein levels were elevated and more concentrated in nuclei in cells in which JAK/STAT signaling is active, such as the border cells (Figs 1, 2), indicated that the STAT protein level and subcellular distribution can be used to detect the level of pathway activity. Therefore, we stained egg chambers in which endocytosis was inactivated in border cells to see whether endocytosis normally increases, decreases, or has no effect on JAK/STAT signal transduction. The effect was dramatic. STAT protein levels were higher overall in border cells expressing dominant-negative dynamin than they were in wild-type border cells, suggesting that endocytosis may normally target some STAT protein for degradation (Fig. 8I,J). However, nuclear enrichment was not as obvious as in wild type (Fig. 8I,J). This could be because endocytosis is required to allow activated STAT to translocate to the nucleus efficiently. Alternatively the level of STAT protein in the nucleus could be similar to in wild type but, because of the higher level of cytoplasmic protein, enrichment in the nucleus is not detected.
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Discussion |
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The ligand for the JAK/STAT pathway, UPD, is expressed in the polar cells
throughout border cell migration (Silver
and Montell, 2001), and we show here that STAT protein is highly
enriched in the nuclei of border cells throughout their migration. STAT
protein was not detected in the central polar cells, suggesting that some
mechanism must exist to attenuate signaling in these cells. This could result
from the expression of an inhibitor of the pathway, or from an absence of
expression of one or more activating components of the pathway.
Using a temperature-sensitive allele of stat, we show that border
cell migration defects become apparent in as little as 30 minutes following
the shift to the non-permissive temperature. These defects become increasingly
severe at longer time points. This result is striking because in order to
observe a defect after only 30 minutes, the cells must stop migrating almost
immediately following the temperature shift. One possibility is that STAT
could be required for the expression of mRNAs and proteins that are very
short-lived and are essential for migration. Alternatively, there might be a
direct role for STAT in cell motility in addition to its well-characterized
function as a transcriptional activator. In support of this possibility, STAT1
and activated STAT3 are found in focal adhesions in mammalian fibroblasts and
ovarian carcinoma cells (Silver and
Montell, 2001; Xie et al.,
2001
). In mammalian cells, STAT3 has also been shown to physically
interact with the active form of the Rac GTPase, which regulates the actin
cytoskeleton (Bar-Sagi and Hall,
2000
; Simon, 2000). In border cells, we showed that overexpression
of UPD, HOP or STAT can suppress border cell migration defects caused by
dominant-negative Rac. Although only genetic interactions have been observed
to date, signaling through the JAK/STAT pathway could provide a means of rapid
activation of Rac in border cells during their migration. It is also possible
that STAT suppresses Rac migration defects indirectly, through a
transcriptional mechanism, as STAT also regulates the expression of two
actin-binding proteins, Singed and Profilin (D.L.S. and D.J.M., unpublished),
and overexpression of Profilin alone is sufficient to suppress
RacN17 migration defects
(Geisbrecht and Montell,
2004
). However, such an effect would presumably require a longer
time course.
Up to two hours following the shift to non-permissive temperature in
statts mutants, border cells showed no detectable
alteration in gene expression. However, in as little as 2.5 hours, expression
of the nurse cell-associated follicle cell marker MA33 was detected in border
cells. This indicates that the border cell fate is extremely labile.
Similarly, germline stem cell fate in the Drosophila testis depends
on JAK/STAT signaling and is labile. When statts flies are
shifted to the non-permissive temperature, the germline stem cells apparently
differentiate (Brawley and Matunis,
2004). The organization of cells at the tip of the testis is
similar to the organization of border cell clusters in that there is a central
group of cells that express UPD. Germ cells that touch the UPD-expressing
cells are exposed to high levels of JAK/STAT activity and remain as stem
cells. Germ cells that become separated from the UPD-expressing cells, and
thus lose JAK/STAT signaling, differentiate. It is unclear how common it will
turn out to be for cell fate maintenance to depend upon continuous input from
neighboring cell types. However, it is easy to see how such a mechanism could
be useful to ensure that the proper ratios of particular cell types are
maintained within a tissue.
Interestingly, the nurse cell-associated follicle cell fate has also been proposed to require STAT activity, albeit a lower level of STAT than border cells (Xi, 2003). Yet, the nurse cell-associated follicle cell fate, as assessed by MA33 expression, did not change after temperature shift at any time point that we examined. Therefore, unlike border cells, this cell fate does not require the continuous activation of the JAK/STAT pathway to be maintained, thus not all STAT-dependent cell fates require sustained signaling. Taken together, these results indicate that continuous signaling through the JAK/STAT pathway is required to sustain border cell motility, as well as to suppress an alternative cell fate.
Regulation of STAT activity
Border cell migration is sensitive to either downregulation or
hyperactivation of STAT activity, as either loss-of-function or
gain-of-function can cause defective migration. STAT activity appears to be
regulated by a variety of mechanisms, including the regulation of protein
abundance and nuclear translocation. It is well established that activation of
JAK leads to nuclear translocation of STAT in mammalian cells (Levy, 2002),
and we also found this to be true in border cells. Our studies also suggest
that activation of the pathway leads to an increase in the overall level of
STAT protein. In wild-type ovaries, we found that STAT protein was enriched in
cells that neighbor the UPD-expressing cells, including stalk cells, border
cells and posterior follicle cells. Furthermore, expression of an activated
form of HOP in a large number of anterior follicle cells led to a dramatic
increase in the level of accumulation of STAT protein in those cells. This
observed increase in STAT protein in response to excess JAK activity is
consistent with previous studies that showed that STAT protein levels are
dramatically reduced, when compared with wild type, in upd, hop and
dome (also called mom) mutant embryos
(Chen et al., 2002), and are
upregulated upon overexpression of UPD and HOPTUM
(Johansen et al., 2003
). Thus,
both the subcellular localization and the overall level of STAT protein
respond to the level of activity of the pathway.
We also provide evidence that the activity-dependent nuclear translocation
and activity-dependent STAT protein accumulation occur via distinct
mechanisms. This conclusion is supported by the finding that, when
receptor-mediated endocytosis was inhibited, STAT protein still accumulated in
border cells, to even higher levels than in wild type. However, nuclear
enrichment of STAT was not observed when endocytosis was inhibited, consistent
with recent pharmacological studies in mammalian cells
(Bild et al., 2002). One model
that is consistent with these findings is that phosphorylation of STAT by JAK
is sufficient to stabilize the STAT protein even without endocytosis. However,
in the absence of endocytosis the phosphoprotein cannot be delivered to the
nucleus efficiently. The receptor Domeless is probably normally actively
recycled in a dynamin-dependent manner, as the protein was readily detected in
puncta within wild-type cells but little in the way of cell surface protein
was observed (this study) (Ghiglione et
al., 2002
). By contrast, in cells expressing dominant-negative
dynamin, cell surface Domeless staining was far more prevalent than
intracellular staining. As STAT did not accumulate specifically at the surface
with Domeless, it is likely that dissociation of STAT from the receptor does
not require endocytosis. EGF receptor signaling is downregulated by
receptor-mediated endocytosis, whereas the results presented here indicate
that endocytosis contributes both positively and negatively to modulate STAT
activity.
In addition to regulation by pathway activation and endocytosis, STAT
activity is controlled by proteins such as SOCS. We found that overexpression
of wild-type SOCS36E inhibited border cell recruitment and migration.
Interestingly, JAK/STAT signaling is both necessary and sufficient for the
expression of SOCS36E in Drosophila embryos
(Karsten et al., 2002).
Together with a recent study that shows expression of SOCS36E mRNA in follicle
cells flanking the polar cells (Rawlings
et al., 2004
), this suggests that SOCS36E may normally function to
achieve the precise level of STAT activity that is required for border cell
migration. Consistent with this, levels of STAT in the border cells were
reduced in egg chambers overexpressing SOCS36E. However, analysis of a
loss-of-function SOCS mutant, which is not yet available, will be the
definitive test of that hypothesis.
Role of UPD and JAK/STAT in organizing the border cell cluster
Normally border cells migrate as a cohesive cluster with the non-migratory,
UPD-expressing cells in the center and the migratory cells surrounding them.
These two cell types are dependent upon each other, as the central cells
cannot migrate and are carried by the surrounding cells, and the migratory
cells cannot move in the absence of the UPD signal from the central cells.
Thus, the organization of the border cell cluster is crucial for normal
migration. In addition to its function in border cell specification and
motility, several lines of evidence demonstrated the role of UPD/JAK/STAT in
organizing the border cell cluster. Ectopic expression of UPD in single
anterior follicle cells, for example, was sufficient to recruit adjacent cells
to form a cluster capable of migration. In addition, we and others have shown
that a variety of treatments that reduced STAT activity (dome mosaic
clones, overexpression of dominant-negative Dome, and overexpression of SOCS)
lead to disruptions of cluster formation
(Ghiglione et al., 2002).
Disruption of the cluster is likely to affect migration through the egg
chamber. For example, PAR6, an epithelial protein required for polarity and
the migration of border cells, is disrupted in border cells in which
dominant-negative Dome is overexpressed
(Pinheiro and Montell, 2004
),
lending support to the idea that JAK/STAT signaling helps to regulate the
organization of cells within the cluster. Once the cluster is disrupted, the
migratory cells become separated from the polar cells, presumably reducing
STAT activity further and aggravating the migration defect. Thus, STAT
activity promotes cluster organization, which feeds back to promote efficient
UPD/DOME/JAK/STAT signaling.
Although ectopic expression of the normal, secreted form of UPD in a single
anterior cell was sufficient to recruit an adjacent cell to form a small
cluster, a single cell expressing the membrane-tethered form of UPD could
recruit two to three cells. One explanation for this difference could be that
the membrane-tethered protein becomes more concentrated locally, as presumably
it cannot diffuse away. A polar cell pair can recruit six cells, suggesting
that polar cells are able to concentrate UPD and limit its diffusion. UPD has
been reported to bind to the extracellular matrix and to stay associated with
the membranes of cultured Drosophila cells
(Harrison et al., 1998). Polar
cells may express higher levels of one or more extracellular matrix proteins
than other anterior follicle cells, allowing them to retain UPD so that
sufficient numbers of migratory cells are recruited.
Taken together, the results presented here demonstrate several inter-related properties of JAK/STAT signaling in the control of border cell migration and function. Both anatomical and biochemical mechanisms feed back upon each other to regulate the level of STAT activity precisely throughout the six hours of border cell migration. Positive-feedback mechanisms include maintaining close contact between UPD-expressing cells and the migratory cells, as well as stabilization and nuclear enrichment of STAT protein in response to signaling. One negative regulatory mechanism is the expression of SOCS36E.
The findings described here may also have relevance for understanding the
requirement of STAT signaling in the progression of cancer. Constitutively
activated STAT3 is associated with the aggressive clinical behavior of a
number of cancers, including ovarian and renal cancers
(Horiguchi et al., 2002;
Huang et al., 2000
). Blocking
STAT3 in pancreatic cancer cells inhibits tumor growth and metastases in mice,
whereas expression of activated STAT3 promotes metastasis
(Wei et al., 2003
). Inhibiting
STAT3 expression or activation in ovarian carcinoma cells impedes their
motility in vitro (Silver et al.,
2004
). Thus, cancer cells too appear to require sustained
activation of this pathway to survive, proliferate and migrate. The finding
that JAK/STAT signaling appears to be tightly regulated by its own activity,
by that of SOCS inhibitors and by endocytic processes suggests that these may
provide points of clinical intervention in the treatment of STAT-dependent
cancers.
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ACKNOWLEDGMENTS |
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Footnotes |
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Supplementary material for this article is available at http://dev.biologists.org/cgi/content/full/132/15/3483/DC1
* Present address: NHGRI, NIH, 49 Convent Drive, Room 4A51, Bethesda, MD
20892, USA
Present address: Stowers Institute, 1000 East 50th Street, Kansas City, MO
64110, USA
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