Department of Molecular and Cellular Biology, Harvard University, Cambridge MA 02138, USA
* Author for correspondence (e-mail: kunes{at}fas.harvard.edu)
Accepted 3 February 2004
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SUMMARY |
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Key words: Glia, Drosophila, Axon, Migration
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Introduction |
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Drosophila melanogaster has been a favorable model system in which
to study cell migration. Genetic analysis has been applied to the mechanisms
controlling movement of follicle cells around the developing oocyte (reviewed
by Montell, 1999) and gonadal
precursors to the site of the developing gonad
(Deshpande et al., 2001
;
Stein et al., 2002
). In the
nervous system, there are many instances of neuronal and glial migration from
sites of cell birth to the locales of developmental and mature function, both
in the CNS (Klambt et al.,
1991
; Klambt,
1993
) and PNS (Giangrande,
1994
; Choi and Benzer,
1994
; Sepp et al.,
2000
).
It is evident that the migration of neural cells to proper destinations can
be a complex process, even in the relatively simple nervous system of the
fruit fly. The adult Drosophila visual system contains glia of many
distinct types and properties that are localized to specific sites in the
retina and optic lobe (Tix et al.,
1997; Saint Marie and Carlson,
1983
; Trujillo-Cenoz,
1965
). Some glia subtypes arise from progenitors located at sites
well removed from their mature positions. Retinal basal glia arise from
progenitors located in the optic stalk, the epithelial tube that connects the
developing eye and brain. Basal glia precursors migrate to the basal surface
of the retina (Choi and Benzer,
1994
; Rangarajan et al.,
1999
). In the optic lobe, lamina epithelial and marginal glia
migrate to their specific layers from progenitor zones located at the
prospective dorsal and ventral margins of the ganglion
(Perez and Steller, 1996
;
Huang and Kunes, 1998
). This
migration depends on local signaling from the photoreceptor axons, as it
largely fails to occur in mutants that do not produce photoreceptor neurons
(Perez and Steller, 1996
) or
are deficient in the activity of the COP9 signalosome
(Suh et al., 2002
).
Conversely, lamina glia are required for the guidance of photoreceptor axons,
and provide an essential stop signal for the R1-R6 subset of photoreceptor
axons to terminate their outgrowth in the lamina
(Poeck et al., 2001
). These
complex processes are controlled with precision in the three-dimensional
milieu of the developing brain by mechanisms that remain unclear.
An important aspect of glial cell migration is the targeting of particular subtypes to specific layers of the developing ganglia. Given their common origin in dorsal and ventral margin progenitor zones, selective mechanisms would be needed to direct glia to different destinations. We show that specific highways for migration are provided by axons that originate in the vicinity of glial progenitors. Photoreceptor axons induce the outgrowth of these `scaffold axons' upon their arrival in the brain, and targeted migration follows. These observations describe a cellular mechanism for the control of optic lobe glial migration by photoreceptor axons, an important element in the coordinated assembly of the precise neural architecture of the optic lobe.
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Materials and methods |
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Immunocytochemistry
Third larval instar-staged animals were examined immunocytochemically
essentially as described by Kunes et al.
(Kunes et al., 1993). Primary
antibodies were used at the following dilutions: mouse anti-Repo 1:10, goat
FITC anti-HRP (Cappel) 1:200, rabbit anti-ß-gal (Promega) 1:500, mouse
anti-glial cells missing 1:100, monoclonal rabbit anti-human caspase
3 (BD PharMingen) 1:100 and rat anti-Elav 1:25. Secondary antibodies were used
at the following dilutions: Cy3 or Cy5goat anti-mouse (Jackson Immunochemical,
Inc.) 1:100, Cy3 or Cy5-goat anti-rabbit (Jackson) 1:500, HRP-conjugated goat
anti-mouse IgG (Jackson) 1:100. Specimens were viewed on a Zeiss LSM510 META
confocal microscope.
Mosaic analysis and crosses
Mosaic analysis was carried out as described by Xu and Rubin
(Xu and Rubin, 1993). Larvae
were subjected to heat shock at 37°C for 5-7 minutes 24-36 hours after
hatching to induce expression of an hsFLP transgene. After growth at 20°C,
larvae were dissected at late third instar stage and processed for
immunohistochemical analysis. The following crosses and strains were used in
the experiments described:
(`>' indicates the position of an FRT site in the respective construct.)
Quantitative analysis of apoptotic cells
Quantification of apoptotic cells in sine oculis and wild-type
animals relied on carefully matched confocal and developmental parameters.
Optical slices (1.3 µm) were compared for age-matched specimens at a
similar focal plane for all specimens analyzed. The number of apoptotic cell
profiles in 50 µm2 regions both proximal to the medulla
neuropile and within the medulla cortex of sine oculis and wild-type
animals were counted. Cortical neuron size (3 µm) and overall brain
size did not differ between sine oculis and wild-type animals, so
cell counts were not biased by any intrinsic differences in cell sizes between
these two genetic backgrounds. Differences in the number of neuropile-proximal
and cortical apoptotic cells in sine oculis animals relative to
wild-type animals were evaluated for significance using Student's paired
t-test.
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Results |
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The wg-lacZ positive extensions are evidently axons. Their cell
membranes were labeled by anti-horseradish peroxidase antibody, a neuronal
marker (Fig. 1C)
(Jan and Jan, 1982). Their
cell bodies were labeled by Elav, also a neuronal marker
(Fig. 1F)
(White et al., 1983
). The
axons extending toward the same neuropile destination were bundled together in
a fascicle, as indicated by labeling of individual axons in mosaic animals
(described below; see Fig. 4). Four wg-lacZ labeled fascicles were resolved emerging from each of
the dorsal and ventral Wg domains (Fig.
1A,B). One fascicle from each domain extended to the border of the
lamina field, terminating at a position adjacent to layers of glia known as
the lamina epithelial (Ep) and marginal (Ma) glia [established nomenclature
(http://www.flybrain.org,
Accession Number PP00003)] (Tix et al.,
1997
). These layers of glia lie, respectively, above and below the
layer the axon termini of the R1-R6 photoreceptors. Glia could be observed
migrating in a chain along the fascicles
(Fig. 1D, between arrowheads).
Owing to the absence of specific markers, we could not distinguish epithelial
and marginal glia prior to their separation into distinct layers. It seems
likely, however, that both glial types migrate on the same pathway. One
fascicle from each Wg domain extended to the cortex, neuropile boundary of the
medulla, and was associated with the chain-like migration of medulla neuropile
(MNG) glia. One fascicle from each domain extended to the boundary between the
medulla and lobula, and corresponded to a pathway for migration of inner
chiasm (Xi) glia, which demarcate the border between medulla and lobula
neuropiles (Tix et al., 1997
).
The final pair of fascicles extended into the lobula neuropile
(Fig. 1F) and formed a pathway
associated with lobula neuropile glia (LoG). We will refer to these four sets
of putative migratory guides as `scaffold axons'. Notably, the migration of
these four glia types depends on retinal innervation of the optic lobe, a
requirement that is explored below.
|
The wg-lacZ labeled-axons also were examined in pupal stage
animals, where mature axon projections into the optic lobe neuropiles could be
resolved (Fig. 3).
wg-lacZ positive axons could still be detected extending from cell
bodies located at dorsal and ventral cortical positions. The axons projected
to respectively dorsal and ventral targets in the medulla and lobula
neuropiles (Fig. 3A,B). It is
evident that the wg-lacZ-positive neurons include intrinsic neurons
of the proximal medulla (Pm neurons), which extend arbors tangentially within
small regions of the proximal medulla
(Fischbach and Dittrich,
1989). Projections into a specific tangential layer of the lobula
were also observed. Projections into the lamina neuropile were not observed;
at the third instar stage the extensions terminate at the border of the
developing lamina neuropile. These axons thus may not have become part of
lamina circuitry, or alternatively have ceased wg-lacZ expression at
the pupal stages examined.
|
By performing clonal analysis with tissue labeled to provide positional
landmarks, it was possible to localize glial progenitors and scaffold neurons
to distinct sites of origin (Fig.
4B; Table 1). The
FLP/FRT system (Golic and Lindquist,
1989; Xu and Rubin,
1993
) was used to generate somatic clones that were positively
marked by membrane-bound GFP (UAS-CD8::GFP)
(Lee and Luo, 1999
). Rare
recombination events were induced such that most specimens harbored only one
or a few labeled cell clones in the developing optic ganglia, which were
examined in late third instar larvae. As reported by Perez and Steller
(Perez and Steller, 1996
),
clones including lamina marginal and epithelial glia were found to label
progenitors located at the dorsal and ventral margins of the outer anlagen
(Fig. 4F,I). Clones that
included lamina epithelial glia, lamina marginal glia, medulla neuropile glia,
inner chiasm glia or lobula neuropile glia were all found within the domain of
cells that express Wg, Omb and Ds (Domain I;
Fig. 4A;
Table 1). A majority of these
clones contained both labeled scaffold neurons and glia (16/26); clones with
only neurons or glia were less frequent. In the majority of specimens in which
glia were labeled, the clone extended into multiple domains and included
Domain I. With rare exception, these larger clones also contained neurons.
Thus, at the time that somatic recombination was induced (the mid-second
instar, 75 hours AEL (after egg laying)), most progenitor cells retained the
potential to produce both neurons and glia. When the specimens were analyzed
with respect to the glial types that were labeled, an interesting pattern
emerged with regard to the position of labeled progenitor cells in the Domain
I region. Labeled progenitors for each of glial cell type appeared in distinct
domains on the proximal, distal axis (Fig.
4B). For example, the lamina epithelial and marginal glial
progenitors were found in a more lateral position
(Fig. 4F) than medulla
neuropile glial progenitors (Fig.
4G). Inner chiasm glial progenitors were observed in an even more
proximal location (Fig. 4H).
Hence, the progenitor domains for distinct glial types appear to be organized
into a proximal distal stack within Domain I, as illustrated in
Fig. 4B.
|
Photoreceptor axons induce the outgrowth of scaffold axons
The migration of glia from the prospective dorsal and ventral margins of
the developing optic lobe depends on the arrival of photoreceptor axons in the
target field (Perez and Steller,
1996; Huang and Kunes,
1998
). When photoreceptor axons are absent, as occurs in mutants
that eliminate ommatidial development (sine oculis, eyes absent and
eyeless) most glia remain stalled in their progenitor domains
(Perez and Steller, 1996
).
When photoreceptor axons innervate only part of the lamina field, glia migrate
to the region that receives retinal innervation. It has thus been supposed
that photoreceptor axons attract glia into the lamina target field. We thus
thought it might be informative to examine the glial migratory scaffold under
conditions where glial migration did not occur.
To this end, the axon scaffold was examined in sine
oculis1 (so) and EyelessD
(ey) animals. These mutants display variable penetrance, such that
photoreceptor neurons can be completely absent, or develop in variably sized
clusters in a particular region of the developing retina. A lack of retinal
innervation has compound effects on optic lobe development. Lamina neurons
fail to develop because of the absence of axon-borne signals
(Selleck and Steller, 1991;
Huang and Kunes, 1996
). The
medulla is greatly reduced in cell number by extensive apoptosis
(Fischbach, 1983
). Employing
mosaic analysis, Fischbach and Technau
(Fischbach and Technau, 1984
)
showed that so1 acts in the eye to bring about these
effects on the brain.
In our analysis, the scaffold axons were labeled by the expression of
wg-lacZ (Fig. 5). When
photoreceptor axons were absent, the scaffold axons were likewise missing
(Fig. 5B). However,
wg-lacZ positive cells seemed to be present in normal number in the
Wg domains (compare Fig. 5A'' with
5B''), and expressed the neuronal HRP antigens (e.g. the
ventral Wg domain in Fig. 5C).
In prior work, a number of markers expressed in the vicinity of the Wg domains
were expressed normally in the absence of retinal innervation (e.g. Dpp and
Omb) (Huang and Kunes, 1996;
Huang and Kunes, 1998
).
Therefore, we think it unlikely that retinal innervation is required for the
differentiation of these optic lobe neurons. When the scaffold axons were
absent in so1 and eyD animals, glia
accumulated at the edges of the Wg domains near the point where they would
have joined axon fascicles on paths toward neuropile destinations (arrowheads
in Fig. 5B',C').
Most so1 and eyD animals develop part
of an eye, such that the corresponding optic lobe receives partial
innervation. In these cases, photoreceptor axons project to appropriate
retinotopic locations despite the absence of the usual array of neighboring
axons (Kunes et al., 1993
). In
such specimens, scaffold axons were found only in parts of the brain that
received retinal innervation and not in regions that completely lacked
innervation (Fig. 5C). Thus,
for example, in the specimen shown in Fig.
5C, photoreceptor axons innervate the dorsal half of the
developing optic lobe where scaffold axons have extended to the medulla
neuropile, and medulla neuropile glia have migrated to normal positions. The
ventral half of the optic lobe by contrast lacked retinal innervation.
Scaffold axons and medulla neuropile glia were correspondingly absent; glia
stalled at their exit point from the Wg domain (arrowhead in
Fig. 5C). A correlation between
retinal innervation, scaffold axon extension and glial migration was found in
each of 32 so1 animals with partial eye development
restricted to either dorsal or ventral regions. These observations thus argue
strongly that scaffold axon outgrowth and glial migration depend on retinal
innervation.
|
In the first approach, we used the ectopic expression of a dominant
negative Ras protein (Ras1N17)
(Lee et al., 1996), which was
found to autonomously block the outgrowth of scaffold axons
(Fig. 6D,E). The
UAS-Ras1N17 transgene was expressed in small somatic
clones that were labeled by the co-expression of UAS-CD8::GFP.
Occasional somatic clones of Ras1N17-expressing cells within the Wg
domain region resulted in failure of scaffold axons to extend toward glial
destinations. By contrast, clones that labeled lamina epithelial, marginal or
medulla neuropile glia did not affect their respective migration (data not
shown). When the scaffold axons were absent, glia stalled prior to migrating
into the neuropile regions, as they did in so1 animals
(arrowheads in Fig. 6D,E). That
is, glia did not migrate when the scaffold axons were missing, even though
retinal axons were present in the target field. These observations indicate
that the scaffold axon fascicles are required as migratory guides for glial
migration.
|
Scaffold axons did indeed project aberrantly in the mutants
ds1 and ds33k
(Fig. 6B,C) and glia lined
these aberrant pathways and accumulated in abnormal destinations. In the
ds1 homozygous animal shown in
Fig. 6B, scaffold axons which
should project toward the medulla neuropile and form a path for medulla
neuropile glia (as shown in Fig.
6A) were found extending toward the lobula cortex. Glia formed a
chain along the aberrant axons (Fig.
6B') and accumulated abnormally in the lobula, while the
number that reached the medulla was reduced. In the ds33k
homozygous animal shown in Fig.
6C, the dorsal scaffold axons bifurcate and appear to direct glia
away from paths toward neuropile destinations. Mutations in combgap,
a negative regulator of optic lobe ds expression
(Song et al., 2000) resulted
in similar axon misrouting and glia distribution abnormalities (data not
shown). The correlation between patterns of scaffold axon misprojection and
glia migratory paths is a further indication that scaffold axons serve as
migratory guides.
The migration of medulla neuropile glia is required for cortical cell survival
Prior work revealed extensive apoptosis in the optic lobes of `eyeless'
mutants of Drosophila (Fischbach
and Technau, 1984; Fischbach
1983
). In the mutant sine oculis (so), mosaic
analysis has revealed that extensive cell death in the optic lobe is due to
the lack of so function in the retina and not the brain. These and
additional observations have led to the conclusion that the optic lobe
phenotype of sine oculis is due to lack of retinal innervation. The
`trophic' function of photoreceptor axons could be direct, via provision of a
survival factor, or indirect, e.g. by eliciting the migration of glia that
provide a survival factor. We explore these distinct hypotheses below.
To address the issue, wild-type and so1 animals were
examined for the onset of apoptosis by their expression of activated caspase,
which can be monitored in Drosophila with an antibody against the
activated human caspase 3 protein (Baker
and Yu, 2001). In third instar stage wild-type animals, few
cortical cells are labeled by the anti-Caspase labeling
(Fig. 7A''). By contrast,
so1 third instar larval optic lobes displayed an increased
number of caspase 3-positive cells throughout the medulla cortex
(Fig. 7B). Putative apoptotic
cells were concentrated in regions where glia were particularly few or absent.
Caspase 3-positive cells were also particularly prevalent in cortical areas
immediately adjacent to the neuropile (arrowheads in
Fig. 7B'). As noted
above, areas particularly deficient in glia also displayed an irregular
neuropile structure. These observations were subjected to a quantitative
analysis (see Materials and methods). Areas of 50 µm2 in 1.3
µm confocal optical sections of the medulla cortex were counted for the
number of caspase 3-positive cells. In wild-type animals, an average of 0.6
(±1, n=10) activated caspase-positive cells were found per 50
µm2 area. No regional differences in the density of apoptotic
cells were observed in wild-type animals. so1 specimens
displayed an average of 5.5 (±2.9; n=37) apoptotic cells in 50
µm2 areas adjacent to medulla neuropile regions that lacked
medulla neuropile glia. Elevated apoptosis, an average of 6.5 (±5.2
n=37) activated caspase-positive cells, was also observed in distal
cortical cell populations whose axons would normally innervate glia-starved
regions of neuropile. By contrast, cell populations adjacent to glia-rich
regions of medulla in the same so1 animals showed only 2.4
(±2.5 n=37) apoptotic cells per 50 µm2, while in
the corresponding distal cortical cell populations that innervate these
glia-rich regions, only 2.5 (±3 n=37) apoptotic cells per 50
µm2 were found. Thus, although so1 animals
displayed an overall increase in caspase-positive cells, the frequency was
significantly greater in cell populations that innervated glia-starved regions
of neuropile. The results of this analysis are statistically significant: for
medulla neuropile proximal regions within so1 animals a
paired t-test analysis yielded a P-value of
1.3e-06 (comparing glia-poor and glia-rich regions), while the same
statistical analysis comparing cortical regions yielded a P value of
4.8e-07. Our observations suggest that both local and long-range
trophic cues are provided by glia to cortical neurons.
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Discussion |
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We show in this report that Drosophila optic lobe glia use axon
fascicles as migratory guides and that the extension of these axon fascicles
is induced by the ingrowth of photoreceptor axons from the developing retina
(Fig. 5). The migratory
scaffold axons emerge from optic lobe regions that are in close proximity to
sites where glial cells originate; both arise in the dorsal and ventral
domains where cells express the morphogen Wingless (Figs
1,
4)
(Kaphingst and Kunes, 1994).
When the scaffold axons were eliminated by the autonomous expression of an
activated Ras transgene, glia failed to migrate and stalled at the borders of
their progenitor sites (Fig.
6). Extensive cortical cell apoptosis ensued
(Fig. 7). When the scaffold
axons projected aberrantly (in animals mutant for the cadherin Dachsous;
Fig. 6), glia followed the
aberrant routes to incorrect destinations. The longstanding observation that
glial migration does not occur in eyeless mutant Drosophila
(Perez and Steller, 1996
;
Huang and Kunes, 1998
) might
thus be explained by an indirect mechanism in which innervation controls the
establishment of an axon scaffold necessary to direct glial migration.
The migratory scaffold axons were identified by their cytoplasmic
expression of ß-galactosidase from lacZ under the control of a
wingless promoter (Kassis et al.,
1992). The neurons are thus residents of the Wg domains, a point
additionally supported by labeling small numbers of neurons that projected
their axons toward glial destinations (Fig.
4). In total, four different wg-lacZ delineated pathways
were identified. These appear to account for all the pathways taken by optic
lobe glia that have been identified as migratory by clonal studies. Separate
pathways were identified for medulla neuropile glia, lobula neuropile and
inner chiasm glia. A single scaffold axon pathway was observed leading to the
marginal and epithelial glial layers of the lamina, suggesting that both of
these glial types follow the same pathway. Perhaps these glia become separated
only on the interposition of photoreceptor R1-R6 growth cones as they arrive
in the lamina. Whether the epithelial and marginal glia arise from distinct
precursors that migrate on the same pathway is unclear. In all cases, glia
were observed to form migratory `chains' along axonal extensions, resembling a
similar organization of migratory glia on retinal axons en route from the
optic stalk to the eye field (Choi and
Benzer, 1994
) and from midline progenitor sites to destinations in
the PNS (Sepp et al., 2000
).
In pupal stage animals, the wg-lacZ labeled neurons were observed in
dorsal and ventral cortical locations, sending projections into neuropile
targets consistent with the patterns of glial migration. However, no axons
from wg-lacZ positive neurons were observed extending into the lamina
neuropile at this stage.
The optic lobe regions surrounding the Wg domains display complex patterns
of gene expression, mainly because of the signaling activity of Wingless
(Kaphingst and Kunes, 1994;
Song et al., 2000
). Our clonal
analysis indicates that all five migratory glial cell types we examined arise
from these domains (Fig. 4 and
Table 1). Interestingly, the
sites from which particular glia arise are stacked on the proximal distal axis
(Fig. 4B) in a manner that
correlates with target destinations in the developing ganglia. Thus, for
example, somatic clones that label the medulla neuropile glia are located at a
position that corresponds to the medial/distal position of MNG glia relative
to the lamina and lobula glia. Furthermore, on the basis of their expression
of wg-lacZ, as well as clonal analysis
(Fig. 4), the neurons that
extend scaffold axons arise in close proximity to the sites of glial origin.
Indeed, as somatic clones induced in mid-second instar larval animals often
labeled both scaffold neurons and migratory glia, the glia and neurons must
share common progenitors. It is curious that all of these distinct cell types
express wingless. We have no evidence that axonally transported Wg
functions in optic lobe development, as it does in the development of the
neuromuscular junction (Packard et al.,
2002
). Partial elimination of wg+ activity (by
the use of a conditional wgts allele) did not result in a
specific defect in glial migration in the optic lobe (R.D. and S.K.,
unpublished) but other possible functions of Wg were not addressed by this
analysis.
Early studies on sine oculis mutants
(Fischbach, 1983;
Fischbach and Technau, 1984
)
demonstrated that lack of retinal innervation results in excessive optic lobe
cell death, especially in the medulla, which is reduced to less than half of
its normal volume without innervation
(Power, 1943
). Our analysis
suggests that these earlier observations may be accounted for by a lack of
glial migration. Though apoptosis was generally elevated in the medulla of
animals lacking retinal innervation, a higher level of cell death was found in
regions particularly devoid of medulla neuropile glia
(Fig. 7). This effect could be
produced with retinal axons present when glial migration was blocked by
elimination of the scaffold axons (via Ras1N17 expression).
Therefore, retinal innervation and its inductive effect on neuronal
development in the lamina is not sufficient for survival. Glial migration is
required. A role for glia in neuronal survival has also been documented in the
lamina, where neuronal cell death follows the elimination of glia in animals
carrying a visual system specific allele of repo
(Xiong and Montell, 1995
).
Our observations suggest a developmental mechanism for the control of glial
cell migration that depends on the establishment of an axon scaffold for
guidance of migrating glia (Fig.
8). In normal development, a small number of glia migrate into the
target field of the photoreceptor axon prior to the arrival of the first
photoreceptor axons (Fig. 2)
(Perez and Steller, 1996).
These glia, which migrate independently of retinal innervation, may serve a
necessary early role in photoreceptor axon guidance. They may be targets for
the first retinal axons to arrive in the optic lobe, and provide the first
signals that differentiate the outgrowth termination points of the R1-R6 and
R7/8 axons (Poeck et al.,
2001
). We propose that the first photoreceptor axons to arrive in
the optic lobe elicit outgrowth of the scaffold axons from neurons at the
dorsal and ventral margins. Subsequent migration of glia from the dorsal and
ventral margin progenitors is then both permitted and directed along the
specific pathways of the scaffold. After the erection of the migratory
scaffold, glial migration may be independent of continued photoreceptor axon
ingrowth. On this point, we note that glia migrate into the lamina in
approximately normal number in hh1 animals, in which
ommatidial development ceases after 11-13 columns form at the posterior of the
developing retina (Huang and Kunes,
1998
). Therefore, glial migration may not depend on continued
arrival of new retinal axons in the lamina primordium. Nonetheless, this
observation cannot rule out the alternative interpretation that retinal axons
emit a continuous attractive signal for glial migration that functions in
adjunct with the migratory axon scaffold.
|
The system for glial migration guidance we describe permits diversified cell types to originate from a common site, and yet target specific locations in complex neuropiles. One could imagine that as more complex and diversified neuropiles evolved, relatively simple changes in the developmental pathway of glial progenitors and the projections of scaffold axons would deliver glial support to new structures. This system also has the feature of functioning as a developmental timing `checkpoint' that fine-tunes the general hormonal coordination of imaginal development. Thus, upon their initial arrival in the brain, retinal axons provide a fine level of local cellular control over the movement of glia, preparing the target field for the next steps of optic lobe development.
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ACKNOWLEDGMENTS |
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