1 Centre for the Molecular Genetics of Development, Adelaide University,
Adelaide SA 5005, Australia
2 Department of Molecular Biosciences, Adelaide University, Adelaide SA 5005,
Australia
3 Department of Developmental Genetics National Institute of Genetics, Mishima,
Shizuoka 411-8540, Japan
4 Research School of Biological Sciences, Australian National University,
Canberra, ACT 2601, Australia
* Present address: Laboratory for Neural Network Development RIKEN Center for
Developmental Biology 2-2-3 Chuo Kobe 650-0047, Japan
Author for correspondence (e-mail:
robert.saint{at}anu.edu.au)
Accepted 30 December 2002
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SUMMARY |
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Key words: Gene regulation, Embryogenesis, Glia, CNS, Drosophila, ARID motif, retained, dead ringer
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INTRODUCTON |
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The two characterized classes of glial cells studied so far in the
embryonic CNS of Drosophila are the midline glia (proposed to
correspond to the floor plate of vertebrates) and longitudinal glia
(reminiscent of vertebrate oligodendrocytes). These cells are distinguished on
the basis of their different positions and patterns of gene expression.
Midline glia, which originate from the mesectoderm, depend on expression of
the single-minded (sim) gene and activation of the EGF
signalling pathway for their development
(Hummel et al., 1999;
Klambt et al., 1991
;
Stemerdink and Jacobs, 1997
).
The ultimate phenotype of embryos mutant for genes essential for midline
development is the absence of axon commissures and collapse of the
longitudinal axon connectives.
Longitudinal glia are a heterogenous population of cells, the specification
of which depends on the activity of the gene glial cells missing/glial
cell deficient (gcm/glide). gcm encodes a transcription
factor which binds to a conserved eight nucleotide DNA-binding motif called
the GCM motif (Akiyama et al.,
1996; Bernardoni et al.,
1998
; Hosoya et al.,
1995
; Jones et al.,
1995
; Schreiber et al.,
1997
; Vincent et al.,
1996
). GCM is a master regulator of glial development, acting as a
switch between neural and glial cell fates. GCM performs its function through
activation of the gene tramtrack (ttk), which encodes a
zinc-finger protein that acts as a repressor of neural cell fate
(Badenhorst, 2001
;
Giesen et al., 1997
;
Van De Bor et al., 2000
).
Concomitantly with repression of the neural cell fate, GCM triggers expression
of proteins that mediate glial cell differentiation. These include a GCM
homolog GLIDE2, the ETS domain protein Pointed (PNT), the homeodomain protein
Reversed polarity (REPO) and Locomotion defects (LOCO), a regulator of
G-protein signalling (Campbell et al.,
1994
; Granderath et al.,
1999b
; Halter et al.,
1995
; Kammerer and Giangrande,
2001
; Klaes et al.,
1994
; Klambt,
1993
; Klambt and Goodman,
1991
; Xiong et al.,
1994
). Activation of the expression of another glial-specific
homeodomain protein, Prospero (PROS), in a subset of LG (six out of ten LG per
hemisegment), depends on the activity of the DROP/MSH/Lottchen protein (DR
FlyBase) (Buescher and Chia,
1997
; Doe et al.,
1991
). In gcm and glide2 mutants, all glial
cells acquire a default neural cell fate
(Akiyama et al., 1996
;
Hosoya et al., 1995
;
Jones et al., 1995
;
Kammerer and Giangrande,
2001
). Surprisingly, when PNT, REPO, LOCO or PROS functions are
abrogated, longitudinal glia are still formed, albeit in a spatially
disorganized fashion, indicating a failure to undergo terminal differentiation
(Buescher and Chia, 1997
).
Longitudinal glial cells are involved in the formation of the longitudinal
axon fascicles by aiding navigation of the pioneer axon growth cones and by
directing the fasciculation and defasciculation of axons
(Hidalgo and Booth, 2000).
Moreover, longitudinal glia are essential for follower axon survival during
Drosophila embryogenesis (Booth et
al., 2000
).
The loss of correctly specified glia in either gcm, glide2 or
Drop/MSH/ltt mutant embryos accounts for the severe defects in the
longitudinal connectives observed in these embryos
(Akiyama et al., 1996;
Buescher and Chia, 1997
;
Hosoya et al., 1995
;
Jones et al., 1995
;
Kammerer and Giangrande,
2001
). By contrast, mutations in any of the pnt, repo,
loco and pros genes result in fasciculation defects that are
much weaker than those observed in the gcm mutant embryos
(Buescher and Chia, 1997
;
Granderath and Klambt, 1999a
).
Embryos lacking any of these gene products develop with minor defasciculation
of the longitudinal connectives.
Despite some progress in understanding the specification of the
longitudinal glia, many genes involved in this process remain unidentified and
the role of some of the known genes is not fully elucidated
(Egger et al., 2002). One
candidate for a role in embryonic CNS development is the Drosophila dead
ringer/retained gene (dri/retn, here referred to as
dri) (retn FlyBase), because of its expression in
the embryonic CNS (Gregory et al.,
1996
). dri encodes a nuclear protein with a conserved DNA
binding domain termed the ARID [AT-rich interaction domain
(Gregory et al., 1996
)
(reviewed by Kortschak et al.,
2000
)]. Analysis of the early stages of Drosophila
embryogenesis showed that DRI is involved in aspects of dorsal/ventral and
anterior/posterior axis formation acting either as a repressor or an activator
depending on a particular developmental context
(Valentine et al., 1998
;
Hader et al., 2000
;
Shandala et al., 1999
). Later
in embryogenesis, dri is required for myogenesis and hindgut
development (Shandala et al.,
1999
).
We describe a role for dri in the formation of a functional CNS during Drosophila embryogenesis. We show that dri is expressed in a subset of glial cells as part of the cascade of transcriptional regulation that occurs during glial cell differentiation. dri mutant embryos are shown to exhibit mild defasciculation defects, similar to those caused by LG differentiation defects in pnt, repo, loco and pros mutant embryos. Finally, the dri mutant longitudinal glia are shown to be defective in their ability to migrate along the longitudinal axonal tracts to their proper positions, providing a cellular basis for the observed axon phenotype.
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MATERIALS AND METHODS |
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Antibodies and staining methods
A rat polyclonal antibody raised against a bacterially expressed pGEX-DRI
fusion protein (Gregory et al.,
1996) was used to detect the distribution of DRI in embryos.
Polyclonal anti-ß-gal was obtained from Rockland Immunochemicals
(Gilbertsville, PA), anti-REPO was provided by A. Travers (Laboratory of
Molecular Biology, Medical Research Council, Cambridge, UK), anti-Eve was
provided by J. Reinitz (The University at Stony Brook, NY), the monoclonal
antibodies 1D4 anti-FasII and 1B7 were provided by C. Goodman (University of
California, Berkeley, CA), and anti-GFP was provided by P. Silver (Dana Faber
Cancer Inst, Boston, MA) (Seedorf et al.,
1999
). The monoclonal antibodies 9F8A9 anti-ELAV, 2B10 anti-CUT,
MR1A anti-PROS, 22C10, BP 102 and 4D9 anti-EN were all obtained from the
Developmental Studies Hybridoma Bank (The University of Iowa, Iowa City, USA).
For immunohistochemistry, anti-IgG secondary antibodies conjugated with AP,
HRP, Cy5 and Lissamine-Rhodamine (Jackson ImmunoResearch Laboratories, PA),
and Alexa488 (Molecular Probes, OR) were used. Biotinylated anti-IgG secondary
antibodies and AP-, Lissamine-Rhodamine-conjugated streptavidin (Jackson
ImmunoResearch Laboratories, PA) were used where signal enhancement was
required. Immunohistochemical staining was carried out according to the method
of Foe (Foe, 1989
). Embryos
were mounted in phosphate-buffered saline (PBS) containing 80% glycerol and
viewed with epifluorescence using a Zeiss Axiophot or by confocal microscopy
using a BioRad MRC1000 scanhead equipped with a krypton/argon laser confocal
microscope.
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RESULTS |
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The A/B SPG and MM CBG express dri (Fig. 2). pnt and loco are expressed in the A/B SPG, but not the MM-CBG (Fig. 2C, data for loco are not shown). pros colocalizes with dri in only five LG per hemineuromere, but is absent from the A/B SPG and the MM-CBG (Fig. 2F).
In addition to the dri-positive glia, each hemineuromere has one lateral cell located posterior to the intersegmental nerve root (as revealed by the mAb 22C10 axon marker; Fig. 1A, arrowhead). The origin of these cells is unknown, but they do not express any glial specific marker (Fig. 2A-F) and they project axons along the longitudinal tracts (K.-L. Harris and P. Whitington, personal communication), confirming their identity as interneurons. The nature of these cells and the role of dri in their development is not considered further in this report.
dri is not involved in the neural/glial cell fate
switch
Expression of dri in the embryonic CNS is first clearly detected
at stage 11 in a single cell per hemineuromere, probably corresponding to the
lateral glioblast (data not shown). DRI continues to be expressed while the
daughter glial cells divide and migrate anteromedially
(Fig. 3A).
|
We then tested whether ectopic expression of dri could induce
glial fates in non-glial cells, as has been shown for gcm and
pnt (Bernardoni et al.,
1998; Klaes et al.,
1994
). However, sim-GAL4-induced expression of
dri in midline cells was found not to increase the number of glial
cells, as measured by the expression of repo
(Fig. 3C, compare with 3D).
Furthermore, when dri is driven by the MZ1580-GAL4 enhancer trap line
that is specific for longitudinal glia and their progeny, as well as for MP2
neurones and macrophages, there were no ectopic pros-positive cells
(data not shown). Ectopic expression of dri is therefore not
sufficient to induce a glial cell fate.
Glial differentiation requires repression of the neuronal fate by the 69
kDa Tramtrack isoform (TTK69) (Badenhorst,
2001; Giesen et al.,
1997
). Overexpression of TTK69 in neuronal cells blocks neural
differentiation. To test whether dri is capable of repressing the
neural fate, we drove expression of UAS-dri in the T2-A4 segments
using Kr-GAL4. In contrast to the effect of expressing TTK69, ectopic
expression of DRI did not prevent normal neural differentiation in the CNS or
PNS, as assayed by expression of the neuronal marker, ELAV
(Fig. 3E, between arrowheads).
The normal differentiation of neural cells also suggests that glial cell fate
is not induced by DRI in the Kr-specific domain. Loss of TTK69
results in general derepression of the 22C10 neural specific antigen in
somatic muscles (Giesen et al.,
1997
). In dri mutants, however, this antigen was observed
in its normal pattern, i.e. in a single somatic muscle fibre
(Fig. 3F). These results show
that dri does not induce the glial fate, nor does it repress the
neural cell fate.
Longitudinal axon tracts are defasciculated in dri mutant
embryos
As the next step in exploring possible roles for dri in the LG, we
investigated the organization of the longitudinal connectives. Axon
projections along the VNC and the subsequent formation of longitudinal
connectives depend on the proper function of longitudinal glia
(Hidalgo and Booth, 2000;
Hidalgo and Brand, 1997
).
During formation of the first longitudinal tract, LG navigate ipsilateral
pioneer axons. Upon establishing contacts with axons, glia continue migrating
along the longitudinal bundles, occupying choice points of axon fasciculation
or defasciculation. The final fasciculation pattern can be visualized as three
longitudinal Fasciclin 2 (Fas2)-positive (mAb1D4-staining) bundles on either
side of the midline of stage 15-16 embryos
(Grenningloh et al., 1991
)
(Fig. 4C).
|
This phenotype could arise as a consequence of neural or glial defects.
With the aim of showing the glial-specificity of the dri phenotype,
we attempted to rescue the axon defects by directing expression of
UAS-dri in longitudinal glia using the MZ1580-GAL4 transgene
(Hidalgo et al., 1995).
Unfortunately, overexpression of dri interfered with normal glial
development, causing misplacement of pros-positive cells and severe
defasciculation of axons (data not shown). However, the possibility that the
phenotype arose as a result of an indirect effect of DRI on neuronal
development was ruled out by staining dri mutant embryos with
anti-EVE, anti-EN, mAbBP102 and mAb22C10, and finding no defects in neural
differentiation (data not shown).
Misplacement of longitudinal glial cells in dri mutant
embryos
The fasciculation defects showed that the dri mutant longitudinal
glia were defective in their axon guidance role. To understand the nature of
this defect further, we examined the behaviour of these cells in dri
mutant embryos. In wild-type stage16 embryos, the longitudinal glia form two
flat sheets of cells either side of the midline underlying the dorsal surface
of the axon tracts (Halter et al.,
1995; Jacobs et al.,
1989
; Schmidt et al.,
1997
) (Fig.
5A,C,E). In dri mutant embryos, these cells were found to
occupy a normal position relative to the midline, indicating that the LG had
undergone their appropriate initial anterior-medial migration from their place
of birth at the very lateral edge of the VNC
(Fig. 5B,D). However, a
pronounced defect in spatial organisation of the glia was observed. The mutant
cells were ventrally shifted and not localized to the characteristic flat cell
sheet on the dorsal side of the longitudinal connectives with only one or two
out of ten glial cells per hemineuromere being in any one focal plane
(Fig. 5F, compare with 5E).
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Longitudinal glia exhibit aberrant cell shapes in dri
mutants
To characterize the cellular dri phenotype further, we used the
gcmP1 enhancer trap, which expresses ß-galactosidase, and
monoclonal antibody 1B7, which recognizes both the neuronal and non-neuronal
form of the Neuroglian protein. Comparison between the wild-type
(Fig. 6A-C) and
dri-mutant (Fig. 6D-F)
phenotypes of stage 14 CNS preparations revealed that some glia lose
expression of the cell adhesion protein, Neuroglian
(Fig. 6E,F, arrows).
Significantly, Neuroglian-deficient glial cells show somewhat round shapes
compared with the more elongated wild-type glia
(Fig. 6, compare B with E). Misregulation of the cell adhesion protein Neuroglian might impede cell-cell
contacts leading to cell shape changes and failure of glia to migrate normally
along the axon tracts.
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DISCUSSION |
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Although dri is expressed early in glial development, two lines of
evidence allow us to conclude that dri does not play a role in the
neural/glial cell fate decision. First, ectopic expression studies showed that
DRI cannot induce a glial cell fate in non-glial cells, nor was it involved in
repression of the neural fate during glial cell formation. Second, loss of
dri function was found not to impair the initiation of gliogenesis.
The first axon tracts were established correctly, indicating that the
dri mutation does not cause any dramatic glial cell fate changes. In
addition, dri mutant longitudinal glia were still able to undergo
their initial migration to the correct position relative to the midline and to
navigate the growth cones of pioneer axons. This process depends on the
ability of the Robo receptor, on the glial cell, to recognize the repulsive
Slit signal emanating from the midline
(Halter et al., 1995;
Jacobs et al., 1989
;
Kinrade et al., 2001
;
Schmidt et al., 1997
). Thus,
we conclude that Robo function is not affected in dri mutants.
After the initial migration and pioneer axon navigation, however, the behaviour of dri-expressing glial cells becomes aberrant. The normal final positions of these cells are never adopted and the cells exhibit cell shape defects. The mild misplacement of LG in dri mutants is probably caused by defects in glia-glia and axon-glia contacts, resulting at least in part from downregulation of the glial cell surface marker Neuroglian. These defects may interfere with correct migration of glia along the axon bundles which, in turn, causes the axon tract defects.
What is the molecular basis of the mutant phenotype found in dri
mutants? DRI is a transcription factor, so the link between loss of
dri function and the failure to differentiate properly is likely to
be indirect, mediated through misregulation of dri targets required
for normal longitudinal glial development. The most informative data came from
our analysis of the position of dri in the glial transcriptional
regulatory cascade. In general terms, dri activity was found to be
downstream of gcm and repo, and independent of pnt
and cut. It was also found to be upstream of two genes, loco
and pros, which are essential for normal development of some glial
cells. In this developmental context dri acts as an activator of
downstream targets. A consensus DRI binding-sequence has been defined
(Gregory et al., 1996), but
neither the loco nor pros promoter regions contain such
sequences. This raises the possibility that loco and pros
might be indirect targets of DRI activity in the hierarchy of glial cell
differentiation. Confirmation of this will require further analysis of
loco and pros transcriptional regulation and perhaps the
discovery of additional transcriptional regulatory factors involved in glial
development.
The requirement for DRI in the activation of loco is unexpected.
loco has been found to be a transcriptional target of PNT but not of
REPO (Granderath et al., 2000;
Granderath et al., 1999b
),
while we found that dri expression depends on REPO and not on PNT. It
is possible that expression of loco is co-dependent on PNT and DRI in
some cells and that the reduced level of dri expression observed in
repo mutants is enough to permit loco expression.
The genetic analysis presented here strengthens the hypothesis that there
are different genetic controls for different subsets of dorsal glia. For
example, dri expression in all glial cells requires GCM activation,
but only some of them requires REPO. The REPO-independent
dri-positive cells, two per hemineuromere, appeared to correspond to
the A and B subperineural glia (A/B SPG). These derive from neuroglioblast
NB1.1 (Halter et al., 1995;
Klambt and Goodman, 1991
;
Udolph et al., 1993
),
suggesting that REPO is required only for the expression of dri in
cells derived from the lateral glioblasts. Unlike dri, pnt and its
downstream target loco are not expressed in the MM CBG, which do not
have a lateral glioblast origin. This suggests that there are different
pathways of pnt and dri induction downstream of
gcm.
At least some of these hierarchical transcriptional interactions may
explain the phenotypes observed. The axon and mild positional defects of glia
in dri mutants resemble phenotypes of other known late gliogenesis
factors, such as those observed in pnt, repo, loco or pros
embryos. It is known that early distribution of the glycoprotein Neuroglian is
perturbed in pros mutant embryos
(Jacobs, 1993). loco
encodes a regulator of G-protein signalling (RGS) that has been shown to bind
to a G
i-subunit (Granderath et al.,
1999b
) and could regulate a G-protein signalling pathway involved
in LG migratory behaviour. In addition, expression of Heartless, the
Drosophila FGF receptor, in LG, and similarities between the
loco and heartless mutant phenotypes
(Granderath et al., 1999b
;
Shishido et al., 1997
) leaves
open the possibility that FGF could trigger final migration of glia along the
longitudinal connectives. This hypothesis is strengthen by the recent finding
that subcellular redistribution of Neuroglian from the plasma membrane to
cytoplasm, which normally happens during final glial migration to enwrap axon
bundles, is disrupted in heartless mutants
(Takizawa and Hotta, 2001
).
Alternatively, it remains possible that additional targets of dri
mediate the role of this gene in longitudinal glial differentiation.
Our studies add dri to the list of genes, including pnt, repo,
loco and pros, that exhibit phenotypes that are much milder than
those of the gcm, glide2 and Drop/Ltt genes at the head of
the dorsal glia hierarchy (Buescher and
Chia, 1997; Campbell et al.,
1994
; Giesen et al.,
1997
; Granderath et al.,
1999b
; Halter et al.,
1995
; Kammerer and Giangrande,
2001
; Klaes et al.,
1994
; Klambt,
1993
; Klambt and Goodman,
1991
; Xiong et al.,
1994
). It appears that diversification of these downstream
regulators produces different types of glial cells. Nonetheless, each plays an
essential role in driving the required behaviour of glial cells during CNS
development. In the case of the DRI transcription factor, this role includes
fine tuning the cell shape and migration characteristics of longitudinal glia
that enable them to establish a normal axon scaffold.
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ACKNOWLEDGMENTS |
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