1 Laboratory of Pattern Formation, Institute of Molecular and Cellular
Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-Ku, Tokyo 113-0032,
Japan
2 Laboratory of Structural Information, Institute of Molecular and Cellular
Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-Ku, Tokyo 113-0032,
Japan
3 Institut de Génétique et Biologie Moléculaire et
Cellulaire, CNRS/INSERM/ULP, BP 10142, Illkirch, C.U. de Strasbourg 67404,
France
4 Graduate Program in Biophysics and Biochemistry, Graduate School of Science,
The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo 113-0033, Japan
* Author for correspondence (e-mail: ttabata{at}iam.u-tokyo.ac.jp)
Accepted 12 August 2005
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SUMMARY |
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Key words: dpp, Visual system, Glia, Drosophila
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Introduction |
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The visual system of Drosophila provides a powerful genetic tool
with which to address the molecular and cellular mechanisms underlying these
processes. The visual system comprises a pair of compound eyes and optic
ganglia, which are the visual processing centers of the brain (reviewed by
Meinertzhagen and Hanson,
1993; Clandinin and Zipursky,
2002
; Tayler and Garrity,
2003
). A repeated unit of the compound eye, the ommatidium,
contains eight photoreceptor neurons (R neurons). Axons from photoreceptor R7
and R8 connect to a deeper target site known as the medulla. By contrast,
R1-R6 neurons stop between two layers of lamina glial cells at the bottom of
the ganglion layer known as the lamina
(Winberg et al., 1992
). R
axons provide signals, Hedgehog (Hh) and Spitz, to the lamina neuron
precursors (LPCs) and induce LPC differentiation into lamina neurons, the
future synaptic partners of the R axons
(Huang and Kunes, 1996
;
Huang and Kunes, 1998
;
Huang et al., 1998
). The
lamina glia play a crucial role in the guidance of R1-R6 growth cones, by
serving as an intermediate target of R1-R6 axons
(Poeck et al., 2001
). It has
also been shown that R axons play an important role in the migration of lamina
glia from the progenitor domain (Suh et
al., 2002
). These glia arise from dorsal and ventral marginal
progenitor zones and migrate into the lamina target region.
Although both the importance of lamina glia for R axon targeting and the
mechanism for their migration have been analysed
(Dearborn and Kunes, 2004),
little is known about the signaling mechanisms that regulate the development
of these glial cells. We show that decapentaplegic (dpp)
plays a key role in the process. DPP is a homolog of BMP and is a member of
the TGFß superfamily, which is widely conserved among species and which
plays central roles in diverse cellular and molecular processes (reviewed by
Hogan, 1996
;
Massague and Chen, 2000
). In
Drosophila, DPP provides positional information by acting as a
morphogen (Lecuit et al.,
1996
; Nellen et al.,
1996
) (reviewed by Tabata and
Takei, 2004
). In the vertebrate nervous system, signaling mediated
by BMP family proteins operates in diverse processes during development. For
example, BMP promotes the differentiation of astroctytes from multipotent
progenitor cells, but inhibits the differentiation of neuronal and
oligodendroglial cell types (reviewed by
Mehler et al., 1997
).
In the Drosophila visual system, dpp is expressed in
dorsal and ventral marginal zones via induction by wingless
(wg) (Kaphingst and Kunes,
1994). An optic lobe mutant for dpp shows defects in the
neuropile in the medulla cortex. These defects are presumably caused by a
failure in neuronal cell fate specification of cells in the outer
proliferation center (OPC), i.e. in the neuroblast populations
(Kaphingst and Kunes, 1994
).
However, brains from animals with the same dpp mutant allele also
lack retinal axon input. In turn, this affects multiple steps of visual system
development and makes it difficult to address the other roles of DPP signaling
in the visual system.
We examined the role of DPP signaling in the visual system using clonal
analysis and the targeted expression of inhibitors specific to signaling. We
show that dpp is required for the establishment of correct R-axon
projection patterns via the control of lamina glia development. The expression
of glial cells missing/glial cells deficient (gcm;
also known as glide) is the earliest marker for lamina glia
differentiation (Dearborn and Kunes,
2004). gcm-positive cells, as well as mature glial cells,
are greatly reduced in dpp mutant animals and in animals with clones
mutant for the intracellular components of DPP signaling. Conversely,
overactivation of DPP signaling induces ectopic expression of gcm and
the production of mature glial cells. Taken together, these data suggest that
DPP signaling is required for R axon projection, as DPP signaling mediates the
production of lamina glia, the intermediate targets of the R axons, via the
control of gcm expression.
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Materials and methods |
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Clonal analysis
Medea4 and Medea8 mutant clones
were generated by the FLP-FRT-mediated mitotic recombination system,
as previously described (Xu and Rubin,
1993), in the Minute mutant background; y w;
Medea4 FRT82B/TM6B or y w; Medea8
FRT82B/TM6B flies were crossed to y w hsflp122; FRT82B
Ubi-GFP M (3)w124. The progeny were heat shocked at the first
instar at 37°C for 60 minutes, and dissected in the late third instar.
Overexpression using the GAL4-UAS system was performed at 29°C
except for for UAS-glideDN, which was performed at
25°C.
Immunohistochemistry
Immunohistochemistry was performed as described previously
(Huang and Kunes, 1996;
Takei et al., 2004
). Rat
anti-DAC and rat anti-ß-Galactosidase (ß-GAL) were raised against
synthetic peptides (Hokudo) and diluted 1:100 and 1:4000, respectively.
Anti-Cyclin A was a gift from S. B. Selleck and was diluted 1:200
(Nakato et al., 2002
). Mouse
monoclonal anti-ß-GAL (Promega) was diluted 1:250. The mouse monoclonal
antibodies anti-Caoptin (referred to as mAb24B10 throughout the text),
anti-CUT and anti-REPO were provided from the Developmental Studies Hybridoma
Bank and were used at a 1:10 dilution. Specimens were mounted with Vectashield
Mounting Media (Vector Laboratories) and viewed on a Zeiss LSM510 confocal
microscope.
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Results |
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We compared the expression pattern of dpp-lacZ, an enhancer-trap
allele of dpp (Tabata and
Kornberg, 1994), with the expression pattern of REPO
(Fig. 1D-F). At a stage prior
to glia differentiation and migration, expression of the dpp reporter
is detected in the dorsal and ventral margins of the lamina target region
(Fig. 1D). dpp
continues to be expressed at the margins of the lamina target region
throughout the third larval instar (Fig.
1E,F).
|
When clones were induced in other regions (i.e. the OPC, lamina or
medulla), R axon targeting defects were not observed. In addition, neither CUT
expressed in the medulla (Fig.
2G,H; n=19) nor DAC expressed in the lamina
(Fig. 2I,J; n>20)
were affected in these clones, suggesting that DPP signaling is not required
for the development of these cell types. Furthermore, Cyclin A accumulation in
G2 to early M phase of the cells in the outer proliferation center (OPC) and
the first row of the lamina neurons
(Nakato et al., 2002) was not
affected (Fig. 2L,M;
n=16), suggesting that DPP signaling is not required for cell cycle
progression in the OPC and lamina neuron precursors.
These results suggest that Medea activity is required in the posterior marginal cells for correct R axon targeting. Because this region includes glial cell progenitors and lamina glia have been shown to play an important role in R axon targeting, we assume that these defects could be due to a failure in some aspect of lamina glia development.
Inhibition of DPP signaling in the lamina glia causes defects in R axon projection
To further address the direct role for DPP signaling in optic lobe
development, we analysed the antagonizing effects of DPP signaling by targeted
expression of the negative regulator Daughters against dpp
(Dad) (Tsuneizumi et al.,
1997). We overexpressed Dad in various domains within the
optic lobe using several Gal4 drivers. Defects in the pattern of R
axon projection were observed when optomotor-blind (omb;
bifid - FlyBase)-Gal4 was used as a driver
(Fig. 3B,F). The penetrance of
the phenotype was about 40% (n=41). The expression pattern of
Dachshund (DAC), a marker for the differentiating lamina neurons, was also
impaired, and the lamina failed to form the regular crescent shape
(Fig. 3C,G). omb is
expressed in large posterior domains, including in glial cell progenitors and
in mature glia in the target region (Huang
and Kunes, 1998
; Dearborn and
Kunes, 2004
) (Fig.
3A). Together, these data suggest that DPP signaling is required
in the glial cell lineage for the differentiation/migration of lamina glial
cells, and DPP loss causes the defect of R axon targeting.
Although omb is also expressed in the retinal basal glia, and in
the dorsal and ventral margins of the eye disc, we did not observe significant
defects in R axon projections when DPP signaling was blocked in these cells.
Lamina glia serve as intermediate targets of R1-R6 axons and thus are required
for the establishment of the correct R axon projection pattern
(Poeck et al., 2001).
Therefore, we examined the structure of the lamina glia layer and the
morphology of the cells to investigate whether they are affected by
Dad overexpression. We found that the lamina glia layers were indeed
defective in these brains. Epithelial, marginal and medulla glia layers were
not clearly distinguishable, cells were not regularly spaced
(Fig. 3K) and there was a
defect in the cell shape. Although epithelial and marginal glia have a
cuboidal shape with many small processes
(Poeck et al., 2001
)
(Fig. 3J,J'), the glial
cells failed to develop their characteristic cuboidal shape and look irregular
in these mutant brains (Fig.
3K,K'). Taken together, these results suggest that DPP
signaling controls the development and formation of the regular array of
lamina glial cells.
gcm is expressed from an early step of lamina glia differentiation
The above results show that blocking DPP signaling can disrupt the
formation of the lamina glia layers. Defects in either differentiation or cell
migration of the glial cells can cause these phenotypes. It has been reported
that when migration of the lamina glia is defective, REPO-positive glia get
stuck in the progenitor domain (Poeck et
al., 2001; Suh et al.,
2002
). However, we did not observe such `stuck' cells when DPP
signaling was blocked (data not shown). These results led us assume that DPP
signaling is required for differentiation rather than for migration of the
glial cells.
|
gcm expression was analysed using an enhancer-trap line,
gcm-lacZrA87, which has been shown to faithfully reflect
the expression pattern of endogenous gcm in the embryo
(Jones et al., 1995;
Vincent et al., 1996
).
ß-GAL signal was observed in the glia lineage, including in precursors at
the margin of lamina target region, which is virtually the same pattern as
that described by Dearborn and Kunes
(Dearborn and Kunes, 2004
) when
using an anti-GCM antibody (Fig.
4A,A'). ß-GAL signal was detected in mature epithelial
and marginal glia (Fig. 4C),
which were also positive for omb-Gal4
(Fig. 4B). When cells migrate
into the targeting region, REPO expression is observed
(Fig. 4A,A'). In
addition, gcm expression is seen in the developing lamina neurons
(Fig. 4D). With these markers,
lamina glia differentiation can be monitored right from the stage when cell
fate is specified.
|
|
To address whether this factor in the brain is indeed dpp, we
analysed the brains of dpp loss-of-function mutants
(Kaphingst and Kunes, 1994)
(dppd6/dppd12 carrying
gcm-lacZ). A severe reduction in the number of gcm-lacZ
expressing cells was observed in these brains
(Fig. 4I). These cells
co-express REPO, indicating that they are glial cell populations
(Fig. 4J). There is no R axon
input in brains with this allelic combination of dpp, as this
combination disrupts the normal contribution of dpp to the eye
formation (Wiersdorff et al.,
1996
; Pignoni and Zipursky,
1997
; Curtiss and Mlodzik,
2000
). However, the decrease of gcm- and REPO-expressing
cells was more prominent than that in the so1 mutant,
which also lacks R axon innervations (Fig.
4E,F,I,J). Together, these data suggest that the further reduction
in the number of gcm-expressing cells is due to a reduction of
dpp activity. In addition, gcm expression in these mutant
brains was not completely lost, possibly because they are disc-specific
regulatory mutants that might still have residual dpp activity.
As previously mentioned, Hh induces the differentiation of lamina neurons.
DAC-positive lamina neurons fail to differentiate in
hhbar3, the eye-specific allele of hh
(Heberlein et al., 1993;
Huang and Kunes, 1998
)
(Fig. 4K,L). We observed that
gcm expression and REPO-positive glia differentiation and migration
were still observed in hhbar3 mutant brains
(Fig, 4K,M), which is
consistent with results reported by Huang and Kunes
(Huang and Kunes, 1998
), who
observed REPO expression in hhbar3 mutant brains.
Conversely, gcm expression in the lamina neuron appeared to be
significantly reduced (Fig.
4M). This result suggests that gcm expression in the
lamina depends on Hh, and that its expression is controlled independently in
these two cell populations.
We also observed that there are gcm-positive cells that are
neither REPO- nor DAC-negative, which are not present in the target region of
the wild-type brain. These cells could be glia-type cells that remain in an
immature state, as it has been shown that R axon innervation plays a role in
the terminal differentiation of glial cells
(Perez and Steller, 1996). It
is also possible that these are fated to the lamina but fail to differentiate
because of a lack of R axon innervations.
|
|
Ectopic activation of DPP signaling in the posterior domain induces gcm and REPO expression
The above results suggest that dpp is required for gcm
expression and for differentiation of the lamina glia lineage. We next
investigated whether ectopic activation of DPP signaling induces glia
differentiation. To this end, we expressed UAS-tkvQ253D, a
constitutively active form of tkv
(Wiersdorff et al., 1996),
with an omb-Gal4 driver. An ectopic gcm expression
domain was induced in these brains (Fig.
6F; n=15), and REPO-positive cells were induced inside of
the ectopic gcm domain (Fig.
6H), indicating that overactivation of DPP signaling can induce
ectopic glia differentiation. Thus, cells in the omb domain are able
to express gcm in response to the dpp signal, and
subsequently develop into glial cells when they receive higher-than-endogenous
levels of the signal.
By contrast, when tkvQ253D was expressed in the OPC, neither gcm nor REPO expression was induced (data not shown). This suggests that only cells in the posterior domain of the optic lobe are competent to become glia in response to DPP signaling.
gcm controls differentiation of the lamina glia
From the above results, we conclude that dpp controls gcm
expression in lamina glia progenitors. Given the role of gcm in the
embryo for the determination of glial cell fate, it is likely that
gcm controls the differentiation of lamina glial cells as well. The
gcm gene exists as a cluster with the homologous gene gcm2,
which may act redundantly in some contexts
(Kammerer and Giangrande,
2001). We made use of the UAS-glideDN
construct, which encodes a chimeric protein that combines (1) a DNA-binding
domain that is highly conserved between gcm and gcm2, and
(2) the repressor domain of Engrailed, which renders the chimeric protein
capable of blocking the function of both gcm and gcm2
(Soustelle et al., 2004
). When
glideDN was induced via omb-Gal4, R axon
projection defects associated with defects in lamina morphology were observed
(Fig. 7F,G; n>20).
In these brains, very few REPO-positive cells can be seen in the presumptive
lamina target region (Fig. 7H),
indicating that the differentiation of the lamina glia is compromised. This
defect was not observed with UAS-glideN7-4DN, which
carries a point mutation in the DNA-binding domain that makes the protein
unable to bind DNA (Soustelle et al.,
2004
). These data confirm that the phenotype observed with the
UAS-glideDN is the result of the specific blocking of
gcm function rather than a non-specific effect of the chimeric
protein. Taken together, the results suggest that gcm is indeed
required for lamina glia differentiation.
As mentioned, gcm is also expressed in the lamina
precursors/neurons. To investigate the function of gcm in the lamina,
we expressed UAS-glideDN in the lamina using
NP6099-Gal4 (Hayashi et al.,
2002) (D.U., S.M. and T.T., unpublished)
(Fig. 7I-K). A severe reduction
in the number of DAC-positive lamina cells was observed in this situation
(Fig. 7L,M; n=12). In
such specimens, R-axon projection to the presumptive lamina target field is
still observed, although the pattern is not completely normal
(Fig. 7M).
glideN7-4DN did not cause such defects, again confirming
the specificity of the phenotype. These data suggest that gcm
activity is also required for lamina neuron differentiation.
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Discussion |
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dpp regulates the differentiation of lamina glial cells directly
wg at the posterior-most domain induces the expression of
dpp and omb (Huang and
Kunes, 1998; Song et al.,
2000
). Some wg-expressing cells extend projections
towards the lamina target region. These cells extend scaffold axons along
which the lamina glia migrate (Dearborn and
Kunes, 2004
). Thus, it was possible that the wg signal is
involved in the migration and/or differentiation of lamina glia. However,
partial elimination of Wg activity with a wgts allele does
not cause a specific defect in glia migration
(Dearborn and Kunes, 2004
).
Therefore, wg may play a role in organizing domains in the visual
cortex by activating/repressing various genes, rather than contributing to the
generation of specific cell types (Song et
al., 2000
).
|
The regulation and role of gcm in cells of distinct lineages
In the embryo, gcm initiates the specification of glial cells from
neural cells of various lineages. gcm expression is strictly
controlled to ensure the correct separation of glial versus neuronal cell
fate. Analysis of the cis-regulatory elements of gcm
suggests that gcm expression depends on multiple regulatory elements
to allow the control of lineage-specific transcription and autoregulation
(reviewed by Jones, 2004). Our
analysis suggests that a different situation exists in the optic lobe;
gcm is expressed in the glia and the lamina neuronal cells, and is
required for the differentiation of these cell types. In addition,
differentiation is controlled differently in the lamina and in the glia. In
the lamina, gcm expression seems to be controlled by hh, and
in the glia, by dpp. These results suggest that gcm is
controlled and functioning in a different manner in the optic lobe. Uncovering
the mechanisms of the control and function of gcm would probably
prove an intriguing focus for future research.
DPP signaling in the visual system development
DPP and its vertebrate homolog BMP play crucial roles in many aspects of
development by controlling patterning, cell growth and differentiation. Our
analysis reveals a role for DPP signaling in lamina glia differentiation in
the Drosophila visual system. DPP has also been reported to function
in several aspects of visual center development; for instance, DPP signaling
has been shown to be involved in the proliferation and migration of the
subretinal glia in eye disc development, which plays an important role in the
R axon navigation (Rangarajan et al.,
2001; Hummel et al.,
2002
). In addition, Kaphingst and Kunes
(Kaphingst and Kunes, 1994
)
reported defects in the medulla neuropile in dpp mutant animals,
suggesting a role for dpp in neuronal fate specification.
Furthermore, tkv is expressed in lamina precursor cells just ahead of
the lamina furrow, where these cells meet R axons and start to differentiate
(H. Tanimoto and T.T., unpublished). Although this possibility is one of the
things that prompted us to look for a role of DPP signaling in lamina
development, we failed to uncover any defects when Mad or
Medea clones were generated in the OPC or the lamina. Moreover,
dpp appears to be expressed in the inner proliferation center (IPC),
which will form the lobula, in addition to its expression in the dorsal and
ventral marginal domains. Thus, dpp may be required for some aspects
of lobula development. Unfortunately, this cannot be easily addressed at this
moment because of a lack of appropriate markers. Further study of the
requirements for dpp in the lamina, the medulla, the lobula and other
cell types could lead to a more comprehensive understanding of how DPP
signaling controls differentiation and other events during development of the
visual system.
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ACKNOWLEDGMENTS |
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