Centre for Developmental Genetics, Department of Biomedical Science, University of Sheffield, Western Bank, Sheffield S10 2TN, UK
Author for correspondence (e-mail:
d.strutt{at}sheffield.ac.uk)
Accepted 3 April 2003
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SUMMARY |
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Key words: Drosophila, Planar polarity, Strabismus, Prickle, Dishevelled, Frizzled
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INTRODUCTION |
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It has recently been discovered that Fz becomes asymmetrically localised to
the distal edge of polarising cells of the pupal wing of Drosophila
(Strutt, 2001). It colocalises
in this location with its downstream signalling component Dishevelled (Dsh)
(Axelrod, 2001
;
Shimada et al., 2001
). At the
same time, the Prickle (Pk) LIM-domain protein localises to the proximal cell
edge (Gubb et al., 1999
;
Tree et al., 2002
) and the
sevenpass transmembrane atypical cadherin Flamingo (Fmi, also known as Starry
Night) and the ankyrin repeat protein Diego (Dgo) localise to both proximal
and distal cell edges (Feiguin et al.,
2001
; Usui et al.,
1999
). The data so far reported suggest that the activity of each
of these five proteins is required for each of the others to become correctly
localised. The mechanism of localisation is not fully understood, although it
has been suggested that feedback loops mediated by Fz/Dsh and Pk may be
important (Axelrod, 2001
;
Strutt, 2001
;
Tree et al., 2002
).
A further factor that might be expected to be asymmetric in wing cells is
the product of the Van Gogh/Strabismus (Vang/Stbm)
locus. This gene was identified as being required for planar polarity
throughout the adult cuticle of Drosophila, including the eye and
wing (Taylor et al., 1998;
Wolff and Rubin, 1998
). Its
loss-of-function phenotypes closely resemble those of other genes that produce
asymmetrically localised proteins, and it shows genetic interactions with the
fz and pk loci (Adler et
al., 2000
). Furthermore, we have recently reported that a fusion
of Vang/Stbm to yellow fluorescent protein (Stbm-YFP) becomes asymmetrically
localised during eye development (Strutt
et al., 2002
).
Vang/Stbm encodes a novel protein with four hydrophobic
stretches that probably cross the membrane
(Wolff and Rubin, 1998). The
final three amino acids match the consensus for a PDZ-binding domain (PBM),
suggesting that Stbm might interact with PDZ-domain proteins. Homologues are
found throughout the animal kingdom, including worms, fish, frogs, mice and
humans (Darken et al., 2002
;
Goto and Keller, 2002
;
Kibar et al., 2001
;
Park and Moon, 2002
;
Wolff and Rubin, 1998
). As
most vertebrate homologues have been named `Strabismus', in this report we
will refer to the Drosophila locus by this name.
Studies in vertebrates have demonstrated roles for stbm homologues
in regulating polarised cell movements, in particular convergent extension
during gastrulation and neural tube closure
(Darken et al., 2002;
Goto and Keller, 2002
;
Jessen et al., 2002
;
Kibar et al., 2001
;
Park and Moon, 2002
). Assays
of deleted forms of Stbm in zebrafish and Xenopus embryos suggest
that the putatively intracellular C-terminal region is most likely to be
important for function of the molecule
(Goto and Keller, 2002
;
Park and Moon, 2002
).
Furthermore, vertebrate Stbm has been shown to bind to a vertebrate Dsh
homologue through this C-terminal region
(Park and Moon, 2002
).
Surprisingly, although binding requires the PDZ domain of Dsh, the putative
PBM of Stbm was not required. Furthermore, studies in vertebrates have led to
conflicting conclusions about the importance of the PBM
(Darken et al., 2002
;
Goto and Keller, 2002
;
Park and Moon, 2002
).
In this study, we investigate the role of the Drosophila Stbm protein in planar polarity patterning of the wing. Using both genetic and molecular techniques, we show that Stbm acts in a hierarchy of molecules that lead to the assembly of asymmetric protein complexes. In particular we find that Stbm binds to Pk and regulates its subcellular distribution and levels. Functional dissection shows that this binding requires the C-terminal intracellular domain of Stbm. However, genetic rescue experiments demonstrate that there is no critical role for the putative PBM in Drosophila planar polarity patterning.
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MATERIALS AND METHODS |
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Immunostaining
Immunostaining was carried out as previously
(Strutt, 2001). Primary
antibodies used were mouse anti-ß-gal (Promega), mouse anti-FLAG M5
(Sigma), mouse anti-Myc 9E10 (Santa Cruz), rabbit anti-Pk
(Tree et al., 2002
), rat
anti-Dsh (Shimada et al.,
2001
), mouse anti-Fmi (Usui et
al., 1999
), rabbit anti-Dlg
(Woods and Bryant, 1991
),
mouse anti-Arm 7A1 (Riggleman et al.,
1990
) (obtained from Developmental Studies Hybridoma Bank, Iowa).
Anti-Stbm was raised in rabbits against a bacterially expressed peptide
corresponding to amino acids 406-584, affinity purified against the same
region. Secondary antibodies were conjugated to Alexa-488 or Alexa-568
(Molecular Probes) or Rhodamine-Red-X or Cy5 (Jackson). Unless otherwise
stated, confocal sections are of the most apical regions of pupal wing cells,
representing the average of several confocal image planes for a total image
depth of about 1 µm.
Biochemistry
For transient transfection, COS-7 cells were grown in 24-well plates.
FuGENE 6 (Roche) was used to transfect 200 ng of each plasmid per well, and
cells were either fixed for immunostaining or lysed for immunoprecipitation 24
hours later. All proteins were expressed using CMV promoter plasmids.
Full-length Stbm, FLAG-Stbm (FLAG-tagged at the N-terminus), Stbm-PBM
(Stbm ORF with final three amino acids deleted), CD2-Stbm-Cterm-
PBM
(amino acids 1 to 246 of rat CD2, fused to amino acids 301 to 581 of Stbm),
Dsh and Pk were cloned in pcDNA3.1 (Invitrogen). pCS-Fz and pCS-Dsh-GFP have
been described previously (Tree et al.,
2002
). Myc-Pk was tagged with 6-Myc epitopes at the N terminus by
cloning in the vector pCS2+MT.
For immunoprecipitation, 1/5 of the lysate from a single well was used for each reaction, diluted in IP buffer (20 mM Tris-HCl pH 7.5, 150 mM NaCl, 0.25% Triton X-100, Roche protease inhibitors). Immunoprecipitations were carried out overnight at 4°C using anti-FLAG M2 (Sigma) or anti-Myc 9E10 (Santa Cruz) and protein G Sepharose (Sigma). Proteins were detected on Western blots using affinity purified anti-GFP (Abcam), anti-Myc 9E10 (Santa Cruz) or anti-Rat CD2 OX34 (Serotec), and HRP-conjugated secondary antibodies (DAKO). Detection was using ECL (Amersham) or Supersignal West Dura (Pierce).
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RESULTS |
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We carried out two further controls for the use of the Stbm-YFP transgene. First, we showed that Stbm-YFP localises normally to proximodistal boundaries in the absence of endogenous stbm function (Fig. 1K); and second we found that ubiquitous Stbm-YFP expression is able to rescue the stbm polarity defect in the wing, eye and leg (Fig. 1M and data not shown).
We note that fusion of YFP to the C terminus of Stbm would be expected to mask the putative PBM. Therefore our rescue of stbm phenotypes by Stbm-YFP expression suggests that this motif is not essential for gene function. We confirmed this by expressing a form of Stbm lacking the PBM and found that this also rescues the stbm polarity phenotype in the wing (Fig. 1N).
Stbm, Fmi and Fz promote the apicolateral localisation of planar
polarity proteins
Of the planar polarity proteins so far studied that exhibit asymmetric
apicolateral localisation, in each case tested this localisation partly
depends upon the function of those other planar polarity genes with
asymmetrically distributed gene products
(Axelrod, 2001;
Shimada et al., 2001
;
Strutt, 2001
;
Tree et al., 2002
;
Usui et al., 1999
).
We have previously reported that stbm function is required for
normal Fz asymmetric localisation (Strutt,
2001). Loss of stbm leads to a reduction in apicolateral
Fz-GFP, with the remaining protein showing a hazy distribution with no
proximodistal modulation (Fig.
2A). Loss of fz also disrupts Stbm-YFP localisation, a
reduction in apicolateral levels being observed and no proximodistal
modulation being evident (Fig.
2B). It is known that fmi activity is required for
apicolateral localisation of Fz (Strutt,
2001
) and Dsh (Shimada et al.,
2001
). We find that loss of fmi also greatly reduces
Stbm-YFP apicolateral localisation (Fig.
2D) and loss of stbm somewhat reduces apicolateral
localisation of Fmi (Fig. 2C).
However, loss of fz has only a negligible effect on apicolateral
localisation of Fmi (Strutt,
2001
; Usui et al.,
1999
).
|
Overall, we conclude that Stbm, Fmi and Fz each promote the stable apicolateral localisation of at least a subset of other polarity proteins to the cell cortex (see Discussion). Notably, we find that overexpression of Fmi, Fz or Stbm does not significantly promote apicolateral accumulation of other polarity proteins (Fig. 2G-J), although it does disrupt proximodistal localisation. We interpret this to mean that these factors have specific roles in the apicolateral recruitment of a polarity protein complex, but cannot promote aggregation above normal levels.
Pk and Dsh promote asymmetric proximodistal localisation and
accumulation of polarity proteins
Removal of dsh or pk-sple function results in similar
phenotypes, as regards the subcellular localisation of Fz, Fmi and Stbm
[Fig. 3A-E; see also
(Shimada et al., 2001;
Strutt, 2001
)]. In both
genotypes, levels of apicolaterally localised polarity proteins are close to
normal (although do sometimes appear slightly reduced) and the proteins are
tightly associated with the cell boundaries, but nevertheless no asymmetric
localisation is evident on the proximodistal axis. Thus, unlike Fz, Fmi and
Stbm, neither of these proteins appears to play a major role in apicolateral
recruitment of other proteins.
|
As previously reported (Tree et al.,
2002), increased Pk levels lead to higher levels of Fz, Dsh and
Fmi in apicolateral complexes (Fig.
3G). High Pk also promotes increased apicolateral accumulation of
Stbm-YFP (Fig. 3H). We also
find that elevated Dsh also leads to increased levels of Stbm-YFP in
apicolateral complexes (Fig.
3I), the phenotype being very similar to that caused by
overexpression of Pk.
It has been suggested that elevated levels of Pk result in increased Fz
signalling and that this accounts for higher protein levels in apicolateral
complexes (Tree et al., 2002).
However, we find that overexpressing Pk in a fz mutant background
still results in higher levels of apicolateral proteins
(Fig. 3J), indicating that such
accumulations are not a result of increased Fz signalling. Furthermore,
overexpression of Fz is known to activate Fz signalling
(Krasnow et al., 1995
), but
does not result in similar increased apicolateral accumulation of polarity
proteins (Fig. 2G). It is
interesting to note that the elevated levels of Pk in stbm clones do
not result in increased apicolateral levels of polarity proteins.
Overall, our results suggests that whereas Dsh and Pk do not play a major role in apicolateral recruitment of polarity proteins, they are crucially important for their asymmetric distribution on the proximodistal axis and they also promote increased aggregation or stability of polarity proteins at the cell cortex.
Stbm interacts directly with Dsh and Pk
Our understanding of the respective roles of different planar polarity
proteins in cell polarisation is limited by our lack of knowledge about their
biochemical interactions and functions. We have therefore investigated the
properties of Stbm using in vitro assays.
It has recently been reported that vertebrate homologues of Stbm and Dsh
associate both in vivo and in vitro (Park
and Moon, 2002). As during the later stages of cell polarisation
in the wing, Dsh is localised distally
(Axelrod, 2001
) and Stbm is
localised proximally (this work), the significance of these findings for the
Drosophila system are unclear. We therefore tested whether
Drosophila Stbm could associate with Drosophila Dsh. We
found that Stbm and Dsh associate using two different assays, when expressed
in COS7 tissue culture cells. First, the proteins co-immunoprecipitate
(Fig. 4A) and secondly Stbm is
able to qualitatively recruit Dsh from cytoplasmic vesicles to Stbm containing
membranes (Fig. 5C, note that
under these expression conditions, Stbm is largely associated with the
Golgi).
|
|
Based on a similar heterologous tissue culture assay, it has been reported
that Pk is capable of antagonising the well-characterised interaction between
Fz and Dsh at the cell cortex (Tree et
al., 2002). Consistent with our failure to observe an appreciable
interaction between Dsh and Pk, we also found no effect of Pk co-expression on
recruitment of Dsh to the cortex by Fz
(Fig. 5J). Indeed, transfection
of a four times excess of the Pk expression plasmid relative to the Dsh
expression plasmid still had no effect. We carried out this assay both in COS7
cells, where Fz is able to efficiently recruit Dsh
(Fig. 5I) and in U-2 OS cells
as used in the previous study (data not shown). Currently we are unable to
explain the discrepancy between our results and the previous study. However,
we note that overexpression of Pk in vivo does not reduce membrane recruitment
of Dsh (Tree et al.,
2002
).
Vertebrate studies have indicated that the PBM of vertebrate Stbm is not
necessary for binding to Dsh (Park and
Moon, 2002), consistent with our own findings that the PBM of
Drosophila Stbm is not absolutely required for its function. We now
find that the PBM is not necessary for binding to Drosophila Dsh or
Pk (Fig. 5L,M,O,Q). However,
the binding activity is located within the C-terminal putative intracellular
tail (Fig. 5O,Q), which can
efficiently recruit either protein in the absence of the PBM when tethered to
the outer cell membrane by the heterologous transmembrane domain of rat CD2.
Furthermore, the same CD2-StbmCterm-
PBM fusion protein
co-immunoprecipitates with Pk (Fig.
4F).
As already noted, it is perhaps surprising that Stbm binds to Dsh, as ultimately these molecules become localised to the opposite sides of cells (or cell-cell boundaries) in the developing wing. However, we find that these proteins can colocalise from much earlier in wing development. For example, in the third instar wing pouch where polarity proteins are not visibly asymmetrically localised, Stbm-EYFP and Dsh colocalise in apicolateral regions of the cell (Fig. 5R). This is consistent with Stbm and Dsh directly associating during the symmetric phase of apicolateral polarity protein localisation. However, it is also possible that this colocalisation is due to assembly of randomly orientated asymmetric complexes across cell-cell boundaries (see Discussion and Fig. 6).
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DISCUSSION |
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Studies of protein localisation and genetic dissection suggests that the
process of asymmetric localisation of planar polarity proteins in the wing can
be divided into two parts: first, a phase in which proteins are localised
apicolaterally to the adherens junction zone; and then a second stage in which
molecules become asymmetrically distributed on the proximodistal axis
(Strutt, 2002). Taking our new
data with that already published (Axelrod,
2001
; Feiguin et al.,
2001
; Shimada et al.,
2001
; Strutt,
2001
; Tree et al.,
2002
; Usui et al.,
1999
), we draw a number of conclusions about the mechanisms
responsible.
The three putative multipass transmembrane proteins Fmi, Fz and Stbm all
play important roles in the first step of localising planar polarity proteins
to the apicolateral adherens junction zone
(Fig. 6A). We believe that Fmi
acts at the top of the hierarchy in this process, as, in its absence,
negligible amounts of any planar polarity proteins become apicolaterally
localised (Feiguin et al.,
2001; Shimada et al.,
2001
; Strutt,
2001
; Tree et al.,
2002
) (this work). Stbm is also key, because, in its absence, both
Fz (Strutt, 2001
) and Fmi
recruitment are reduced (this work). Additionally, Stbm is also required for
Dsh apicolateral recruitment and for efficient localisation of Pk to
membranes. Fz is not significantly required for apicolateral recruitment of
Fmi (Strutt, 2001
), but is
partly needed for apicolateral localisation of Stbm and is absolutely required
for apicolateral localisation of Dsh
(Axelrod, 2001
;
Shimada et al., 2001
). Hence,
in the absence of Fmi, Fz or Stbm, one or more planar polarity proteins do not
become apicolaterally localised and the process of asymmetric localisation on
the proximodistal axis does not occur.
An important question is which of these factors are directly binding
together, in the process of apicolateral recruitment. So far no direct protein
interactions have been reported for Fmi, although it is tempting to speculate
that Fmi might bind directly to Fz and Stbm in the process of apicolateral
recruitment. However, Fz is able to recruit Dsh to membranes in a heterologous
cell type (Axelrod et al.,
1998), suggesting that these factors directly interact. In
addition, vertebrate Stbm and Dsh homologues have been shown to directly
interact (Park and Moon,
2002
). We now show direct interactions between Drosophila
Stbm and Dsh, and Stbm and Pk. This suggests a model in which Dsh and Pk both
become apicolaterally localised as a result of direct interactions with Fz and
Stbm. Notably, in the absence of Stbm, Pk accumulates in the cytoplasm,
suggesting that its interaction with Stbm is important for regulating its
level in the cell in addition to its subcellular localisation.
At the stage when the planar polarity proteins are apicolaterally
localised, but prior to the stage when they are asymmetrically localised on
the proximodistal axis of the wing, it is possible that they are present in
either `symmetric' or `asymmetric' complexes assembled across cell-cell
boundaries (Fig. 6B). If the
complexes were symmetric, then Fmi, Fz, Stbm, Pk and Dsh would all be present
in a complex together on the same side of the cell-cell boundary. Such
symmetric complexes would then subsequently evolve into asymmetric complexes,
with Fz/Dsh at distal cell edges and Stbm/Pk at proximal cell edges and Fmi on
both sides. Alternatively, the initial apicolateral complexes formed could be
asymmetric, with Fz/Dsh always on the opposite side of the cell-cell boundary
from Stbm/Pk. These asymmetric complexes would initially be randomly
orientated relative to the axes of the wing, but would gradually become
aligned to the proximodistal axis. We favour the possibility that planar
polarity protein complexes are initially symmetric, as Stbm directly interacts
with Dsh and these molecules colocalise during earlier stages of wing
development. However, it has been reported that Pk and Dsh-GFP do not
precisely colocalise in early pupal wings
(Tree et al., 2002), which
supports the early presence of asymmetric complexes.
After the apicolateral recruitment of planar polarity proteins, over a
number of hours their localisation alters such that they become asymmetrically
distributed on the proximodistal axis of the wing. Although Dsh and Pk play
negligible roles in the apicolateral recruitment of proteins, both are
required for this subsequent proximodistal redistribution. As overexpression
of both factors leads to the accumulation of polarity proteins at apicolateral
cell boundaries, we suggest that they both function to promote the assembly
and/or stabilisation of protein complexes. We note that removal of the
function of the planar polarity gene dgo also blocks asymmetric
proximodistal localisation but not apicolateral localisation of other polarity
proteins (Feiguin et al.,
2001). Furthermore, overexpression of Dgo causes a similar
accumulation of other polarity proteins at cell boundaries to that seen when
Dsh and Pk are overexpressed. Therefore, we propose that Dsh and Pk act
together with Dgo in the assembly of asymmetric complexes.
Recently, it has been proposed that the function of Pk in asymmetric
complex assembly is to antagonise Dsh localisation to membranes
(Tree et al., 2002). This
model is mechanistically attractive, in providing an explanation for the
formation of asymmetric complexes in which Dsh and Pk are found on opposite
sides of cell-cell boundaries. However, we find that in the presence of Stbm,
Dsh and Pk will colocalise at the same membranes. Furthermore, we were unable
to show an effect of overexpressing Pk on the association of Fz and Dsh at
membranes. In addition, high level Pk expression in vivo does not cause Dsh to
lose its membrane localisation but instead appears to increase levels of Dsh
at the membrane (Tree et al.,
2002
). Resolution of these issues will require a more detailed
understanding of the composition and properties of the protein complexes
involved.
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ACKNOWLEDGMENTS |
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Footnotes |
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