McGill Centre for Research in Neuroscience, and Department of Neurology and Neurosurgery, McGill University Health Centre, 1650 Cedar Avenue, Montreal, Quebec H3G 1A4, Canada
* Author for correspondence (e-mail: yong.rao{at}mcgill.ca)
Accepted 17 August 2004
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SUMMARY |
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Key words: Off-track, Neuronal target selection, Layer-specific connectivity, Drosophila visual system
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Introduction |
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The formation of photoreceptor-to-optic-lobe connections in the
Drosophila adult visual system is an excellent and simple model to
study the molecular mechanisms that control the establishment of
layer-specific neuronal connectivity during development
(Clandinin and Zipursky, 2002;
Tayler and Garrity, 2003
). The
Drosophila adult visual system is comprised of the compound eye and
the optic lobe. The compound eye consists of
800 ommatidia or single eye
units, each containing eight different photoreceptor cells (R cells). R cells
project axons into one of two optic ganglion layers in the brain. R1-R6 cells
connect to the superficial layer of the optic lobe, the lamina, and are
responsible for the absorption of light in the green range. While R7 and R8
cells connect to the deeper medulla layer, and are responsible for the
absorption of light in the ultraviolet and blue range. The formation of
layer-specific R-cell connection pattern begins at the third-instar larval
stage. Precursor cells in third-instar larval eye-imaginal discs begin to
differentiate into R cells. Within each ommatidium, the R8 precursor cell
differentiates first and projects its axon through the optic stalk and the
developing lamina into the medulla. Axons from the later differentiated R1-R7
cells within the same ommatidium form a single bundle with the pioneer R8 axon
until they encounter a layer of glial cells (i.e. marginal glia) within the
lamina layer. There they have to make a binary choice: either stop or keep
going into the medulla. The R1-R6 growth cones terminate within the lamina in
response to an unknown stop signal from lamina glial cells
(Poeck et al., 2001
), their
intermediate target at larval stage. By contrast, R7 growth cones extend
further to join R8 growth cones in the medulla. During pupation, R1-R6 growth
cones undergo further stereotyped rearrangements and subsequently form
synaptic connections with lamina neurons
(Clandinin and Zipursky, 2000
;
Meinertzhagen and Hanson,
1993
).
Recent studies have identified several cell surface proteins that are
required for R-cell connectivity. Specifically, N-Cadherin, the receptor
tyrosine phosphatase Lar and the Cadherin-related protein Flamingo have each
been shown to be required for the establishment of local synaptic connections
between R1-R6 axons and lamina cartridge neurons
(Clandinin et al., 2001;
Lee et al., 2001
;
Lee et al., 2003
). An
additional role for N-Cadherin, Lar and the receptor tyrosine phosphatase
PTP69D in R7 axons and Flamingo in R8 axons for forming local connections with
target cells within the medulla has also been reveled
(Clandinin et al., 2001
;
Lee et al., 2001
;
Lee et al., 2003
;
Maurel-Zaffran et al., 2001
;
Newsome et al., 2000a
;
Senti et al., 2003
). However,
loss of N-Cadherin or Flamingo does not affect the initial choice between
lamina versus medulla target selection. In their absence R1-R6 still connect
to the lamina, while R7 and R8 still choose the medulla for establishing
synaptic connections. While loss of Ptp69D or Lar does
affect the initial projections of R1-R6 axons
(Clandinin et al., 2001
;
Garrity et al., 1999
), the
completed pattern of lamina-versus-medulla target selection in adult
Ptp69D or Lar mutants remains largely unchanged
(Clandinin et al., 2001
;
Newsome et al., 2000a
). These
data argue against a direct role for either PTP69D or Lar in specifying
lamina-specific targeting of R1-R6 axons. In addition to the above cell
surface receptors, two Drosophila receptor tyrosine kinases, the
insulin receptor and Eph receptor, are also required for regulating different
aspects of R-cell axon guidance (Dearborn
et al., 2002
; Song et al.,
2003
). However, neither has been shown to play a role in
regulating layer-specific R-cell connectivity. Thus, it remains unclear how
R-cell axons detect layer-specific targeting signals to make the binary
decision for choosing either lamina or medulla to establish synaptic
connections.
In a search for genes that are required for R-cell projections in the
developing visual system, we have identified the receptor tyrosine kinase Otk
as a key determinant in specifying the binary lamina versus medulla target
selection. While Otk was originally isolated based on its homology with the
trk family of neurotrophin receptors in vertebrates
(Pulido et al., 1992), more
recent studies suggest strongly that Otk is not a homolog of the vertebrate
Trk A receptor (Kroiher et al.,
2001
). It has been shown that in vitro Otk mediates
cellcell adhesion in a Ca2+-independent homophilic manner
(Pulido et al., 1992
), while
in vivo it functions downstream of Semaphorin-1a (Sema-1a) to regulate motor
axon guidance at the embryonic stage
(Winberg et al., 2001
). In
this study, we show that Otk is predominantly localized to R1-R6 growth cones
in the fly visual system and is specifically required for lamina-specific
targeting of R1-R6 axons. We propose that Otk recognizes a lamina-derived
signal for R1-R6 targeting.
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Materials and methods |
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Histology and immunohistochemistry
Adult retinae were dissected, fixed and embedded in plastic for tangential
sectioning as described (Tomlinson and
Ready, 1987). Cryostat sections of adult mosaic heads were stained
with mAb 24B10 or anti-ß-galactosidase antibody as described
(Garrity et al., 1996
).
Eyebrain complexes from third-instar larvae were dissected and stained
with antibodies as described (Ruan et al.,
1999
). Antibodies to Chaoptin (24B10) (1:100 dilution, DSHB),
Prospero (1:200 dilution, DSHB), Boss (1:2000 dilution), Repo (1:10 dilution,
DSHB), Otk (1:100 dilution) (Pulido et
al., 1992
), GFP (1:1000 dilution, Molecular Probes) and
ß-galactosidase (1:100 dilution) were used as primary antibodies. For
HRP/DAB visualization, HRP-conjugated anti-mouse and anti-rabbit secondary
antibodies were used at 1:200 dilution. For fluorescent staining, Texas-red-
or FITC-conjugated goat anti-rabbit and anti-mouse secondary antibodies
(Jackson Immunochemicals) were used at 1:200 dilution. Epifluorescent images
were captured using a high-resolution fluorescence imaging system (Canberra
Packard) and analyzed by 2D Deconvolution using MetaMorph imaging software
(Universal Imaging, Brandywine, PA).
The percentage of mistargeted R2-R5 axons or axon bundles in the medulla in
otk and sema mutants was estimated by following the method
described previously (Garrity et al.,
1999) with only minor modification. Since mistargeted R2-R5 axons
were observed in individuals that were much younger than that reported
previously (Garrity et al.,
1999
), the mean number of ommatidial rows were subtracted by four
instead of nine ommatidial rows. R-cell axons projected from these subtracted
younger ommatidial rows presumably had not reached the brain.
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Results |
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R-cell projection pattern in otk mosaic larvae was examined using
monoclonal antibody 24B10, which visualizes all R-cell axons in the developing
optic lobe (Van Vactor et al.,
1988). In wild type (Fig.
1A), R1-R6 growth cones terminated within the lamina and then
expanded significantly in size, which were seen as a continuous layer of 24B10
immunoreactivity within the lamina. Whereas expanded R7 and R8 growth cones
form a highly organized pattern within the medulla. In
otk3 mosaic individuals (n=25 hemispheres,
Fig. 1B), small gaps were
frequently observed in R1-R6 terminal field. The terminal field within the
medulla was also disorganized as thicker bundles were frequently observed
within the medulla. Unlike some known mutations (e.g. dock and
pak) that affect R-cell guidance
(Garrity et al., 1996
;
Hing et al., 1999
), loss of
otk did not cause an obvious defect in the overall organization of
R-cell axons within the developing optic lobe. The formation of topographic
map also appeared normal.
|
Otk is expressed in the developing Drosophila adult visual system
Previous studies demonstrated that Otk is specifically expressed in the
nervous system at the embryonic stage
(Pulido et al., 1992;
Winberg et al., 2001
). To
determine if Otk is also expressed in the developing adult visual system at
larval stage, we stained third-instar larval eyebrain complexes with an
affinity purified anti-Otk antibody
(Pulido et al., 1992
). In wild
type (Fig. 2B,C), anti-Otk
staining was detected on R-cell axons in the developing optic lobe. In the
lamina, the staining overlapped largely with 24B10 immunoreactivity, which
reflects the expression pattern of Chaoptin, a cell surface adhesion molecule
expressed exclusively on all R cells and their axons
(Van Vactor et al., 1988
). The
strongest staining was observed in the lamina plexus, comprised primarily of
R1-R6 growth cones. Although anti-Otk immunoreactivity was also detected in
the developing medulla, we could not tell if Otk is present on R7 and R8
growth cones due to the uniform staining pattern in the medulla neuropil,
which consists of both R-cell and non-R-cell axons
(Fig. 2B,C). The specificity of
anti-Otk staining was supported by the fact that the staining within the
lamina was largely absent in otk3 mosaic larvae
(Fig. 2E,F). We conclude that
Otk is expressed in developing R cells and is localized predominantly to R1-R6
growth cones.
|
|
|
|
Loss of otk severely disrupts the completed pattern of R-cell connectivity in adult flies
To determine the effect of the otk mutation on the completed
pattern of R-cell-to-brain connectivity in adults, we examined R-cell axonal
projections in otk mosaic heads. Again, large clones of
otk3 mutant tissues were generated in the compound eye by
eye-specific mitotic recombination. The completed R-cell projection pattern in
adults was examined by staining frozen sections of otk mosaic heads
with MAb 24B10. Although R-cell axons appeared to project into correct
topographic locations, an increase in the number of axon terminals within the
medulla was observed in all sections examined (n=16 hemispheres)
(compare Fig. 6B,D with
6A,C), suggesting that many
mistargeted R1-R6 axons remained within the medulla.
|
otk is not required for R7 axon targeting
To determine if loss of otk also affects the targeting of other R
cells, we used the adult R7 marker PanR7-GAL4::UAS-Synaptobrevin-GFP to
specifically assess the projections of R7 axons in otk adult mosaic
heads in which the vast majority of R cells are otk mutant cells. In
wild type (Fig. 7A), R7 axons
projected into a region (i.e. M6 layer) in the medulla that is deeper than the
R8 terminal field (i.e. M3 layer). In all sections examined (10 hemispheres),
we found that labeled R7 axons still projected into the correct locations
within the medulla (Fig. 7B).
Thus, unlike loss of Ptp69D or Lar
(Clandinin et al., 2001;
Maurel-Zaffran et al., 2001
;
Newsome et al., 2000a
),
mutations in otk do not affect R7 targeting.
|
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Discussion |
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The role of Otk in R1-R6 growth cones appears to be different from that of
PTP69D, the only other cell surface receptor that has also been shown to be
required for the initial termination of R1-R6 axons within the lamina
(Garrity et al., 1999;
Newsome et al., 2000a
). In
Ptp69D mutants, although
25% of ommatidia projected one or more
R1-R6 axons into the medulla at larval stage
(Garrity et al., 1999
), only a
few axon bundles (32 mistargeted R1-R6 axons or axon bundles in a total of 34
hemispheres examined) remained within the medulla at adult stage
(Newsome et al., 2000a
). In
addition, mutations in Ptp69D also disrupted R7 targeting
(Newsome et al., 2000a
). Many
R7 axons did not project into their normal M6 layer, but instead stayed with
the pioneer R8 axon at the superficial M3 layer within the medulla. These
observations led to the suggestion that PTP69D plays a permissive role in
R1-R6 targeting: that is, PTP69D may mediate defasciculation between R1-R6 and
the pioneer R8 axon in the lamina and between R7 and R8 axons in the medulla,
thus allowing them to respond to a targeting signal. While we cannot entirely
exclude this possibility for the action of Otk, it appears unlikely that R1-R6
targeting error in otk mutants is simply caused by defects in R-cell
defasciculation. Unlike that in Ptp69D mutants
(Newsome et al., 2000a
),
severe R1-R6 targeting errors (one or more mistargeted R1-R6 axons in
42%
of total ommatidial axon bundles) were also observed in otk adult
mutants, whereas R7 target selection remained normal. Moreover, although
mutations in the trio or pak gene caused a severe
hyper-fasciculation phenotype, they did not affect the completed pattern of
R1-R6 connectivity (Hing et al.,
1999
; Newsome et al.,
2000b
). Thus, we favor the model in which Otk is actively involved
in detecting a targeting signal for R1-R6 axons to select the lamina
layer.
While in otk mutants a large number of R1-R6 axons connected
abnormally to medulla, many R1-R6 axons still select the lamina for
establishing synaptic connections. One probable explanation is that the
absence of Otk may be partially compensated by another receptor that also
plays a role in specifying R1-R6 targeting. Partial redundancy is not uncommon
for genes that regulate axon guidance. For instance, it has been shown that
four neural-specific receptor tyrosine phosphastes (i.e. PTP10D, LAR, PTP69D
and PTP99A) are partially redundant with each other in regulating axon
guidance in the fly embryo (Sun et al.,
2001). In mammals, recent studies demonstrate that the
floor-plate-derived morphogen sonic hedgehog cooperates with netrin to guide
commissural axons toward the ventral midline in the developing spinal cord
(Charron et al., 2003
).
Previous studies show that mutations in the brakeless (bks)
(scribbler (sbb) FlyBase) gene caused a more severe
R1-R6 targeting phenotype (Rao et al.,
2000; Senti et al.,
2000
). Most, if not all, R1-R6 axons in bks mutants
projected aberrantly into the medulla. The bks gene encodes a nuclear
protein expressed in all R cells (Rao et
al., 2000
; Senti et al.,
2000
). Later studies by Banerjee and colleagues further indicate
that Bks functions in R-cell growth-cone targeting by repressing the
expression of another nuclear protein, Runt, in R2 and R5 cells
(Kaminker et al., 2002
). These
studies thus raise the interesting possibility that Bks and Runt are
components of a gene expression regulatory pathway, which controls the
expression of specific cell surface receptors on R1-R6 growth cones for
detecting a stop signal from the target region. To examine if the expression
of Otk in R1-R6 cells is dependent on Bks, we examined the level of the Otk
protein in bks mutants. However, no alteration in the expression
level of Otk was detected (data not shown), arguing against Otk as a
downstream target of the Bks pathway.
Although otk is necessary for lamina-specific targeting of R1-R6
axons, its expression in R7 axons was not sufficient to target R7 axons to the
lamina. There are several possible explanations for this result. Otk may need
to collaborate with another cell surface protein that is present on R1-6 but
not R7 growth cones to mediate the lamina-specific targeting decision, and
thus act as a component of a receptor complex. This situation may be similar
to that of the Nogo (Rtn4 Mouse Genome Informatics) receptor complex,
which is involved in inhibiting neurite outgrowth in mammals
(Wang et al., 2002). Upon
ligand binding, the Nogo receptor initiates an inhibitory response only in the
presence of p75 (Ngfr Mouse Genome Informatics), another cell surface
receptor. Alternatively, the signaling components that function downstream of
Otk in R1-6 growth cones may not be present in R7 growth cones. Or the
presence of some inhibitory mechanisms within R7 growth cones prevents them
from responding to an Otk-mediated lamina-targeting signal. The possibility
that Otk plays a permissive but not instructive role in R1-R6 growth-cone
targeting cannot be excluded either.
Previous studies demonstrated that Otk forms a receptor complex with Plexin
A, which functions downstream of Sema-1a during motor axon guidance in the fly
embryo (Winberg et al., 2001).
In the fly adult visual system, however, the sema-1a phenotype
appears quite different from that of otk, as the R1-R6 targeting
pattern remained largely normal in sema-1a mutants (see
Fig. 5). The simplest
interpretation of this data is that otk functions in a different
pathway in R1-R6 growth cones for specifying lamina-specific targeting
decision. An alternative explanation is that Sema-1a may function redundantly
with other proteins (for instance, other members of the Semaphorin protein
family), to regulate the function of Otk during R1-R6 targeting. Our present
data do not allow us to distinguish among these possibilities.
Otk belongs to the evolutionarily conserved CCK-4 family of `dead' receptor
tyrosine kinases (Kroiher et al.,
2001). Members of this family carry alterations in several
evolutionarily conserved residues within the kinase domain that have been
shown to be essential for the activity of most (if not all) active tyrosine
kinases. Indeed, several of them have been shown to be inactive kinases by
biochemical analysis (Miller and Steele,
2000
). How does a defective receptor tyrosine kinase such as Otk
transduce targeting signals for specifying layer-specific R-cell connectivity?
One possibility is that Otk associates with an unknown active tyrosine kinase,
which induces tyrosine phosphorylation on Otk upon ligand binding. One
precedent for this is the dead kinase ErbB3, a member of the vertebrate EGFR
family. Although the kinase activity of ErbB3 is greatly impaired, it can
transduce mitogenic signals by forming a heterodimer receptor complex with
another EGFR family member (e.g. ErbB2) carrying an active kinase domain
(Alimandi et al., 1995
;
Kim et al., 1998
;
Sliwkowski et al., 1994
).
ErbB2 then induces tyrosine phosphorylation in the cytoplasmic domain of
ErbB3, which serves as docking sites for downstream signaling proteins.
Interestingly, it has been shown that Otk is phosphorylated on tyrosine
residues in both fly and mammalian cultured cells
(Pulido et al., 1992
;
Winberg et al., 2001
). It is
highly possible that in response to a targeting signal these phosphorylation
sites recruit downstream signaling proteins, which then transduce the signal
into the termination of R1-R6 growth cones within the lamina. In this context,
it is notable that the intracellular signaling protein Dreadlocks (Dock), a
SH2/SH3 adapter protein, also plays a role in lamina-specific targeting of
R1-R6 axons (Garrity et al.,
1996
). Dock contains a single SH2 domain that can bind to specific
phosphorylated tyrosine residues on activated proteins. Our previous studies
suggest that a Dock-mediated signal activates the Ste20-like kinase Msn, which
in turn phosphorylates the cytoskeletal regulator Bif, leading to the
termination of R1-R6 growth cones in the lamina
(Ruan et al., 2002
;
Ruan et al., 1999
). We have
performed experiments to investigate the potential interaction between Otk and
Dock during R1-R6 targeting. However, we did not observe any genetic
interaction between them (data not shown). Moreover, quantification of the
R1-R6 targeting phenotype in adults shows that the phenotype in dock
mutants was less severe than that in otk mutants (data not shown).
While these data appear inconsistent with the notion that Otk and Dock
function in the same pathway, it does not exclude the possibility that Dock
cooperates with another SH2-containing protein to transduce the signal from
the activation of Otk to downstream effectors for lamina-specific targeting of
R1-R6 axons. Further studies will be necessary to critically address this
matter.
In summary, our present study demonstrates an essential role for Otk in specifying R-cell connectivity. We propose that Otk is involved in recognizing a layer-specific signal for R1-R6 axons to select the lamina for synaptic connections. Further biochemical, molecular and genetic dissection of the Otk pathway will help to understand the action of Otk in R-cell growth cones and shed light on the general mechanisms controlling the establishment of layer-specific neuronal connectivity in the nervous system.
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ACKNOWLEDGMENTS |
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