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First published online 13 March 2008
doi: 10.1242/dev.019117
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1 Laboratory of Pattern Formation, Institute of Molecular and Cellular
Biosciences, the University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-0032,
Japan.
2 Graduate program in Biophysics and Biochemistry, Graduate School of Science,
the University of Tokyo, Hongo7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
Author for correspondence (e-mail:
ttabata{at}iam.u-tokyo.ac.jp)
Accepted 18 February 2008
 |
SUMMARY |
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 TOP SUMMARY INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key words: Drosophila, JAK/STAT, Medulla, Neuroblast, Proneural wave
|
INTRODUCTION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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;
Goodman and Doe, 1993).
Embryonic NBs delaminate as single cells from an epithelium called the ventral
neuroectoderm. Neuroectodermal cells divide symmetrically in the plane of the
neuroectoderm to generate identical daughter cells, but, upon differentiation
into NBs, their axis of division rotates to a vertical plane (perpendicular to
the neuroectoderm). NBs divide asymmetrically to generate a self-renewing NB
and a ganglion mother cell (GMC), which divides again and typically generates
two post-mitotic neurons (Fuerstenberg et
al., 1998; Yu et al.,
2006). Similar mechanisms have been described for vertebrate CNS
development; progenitor cells proliferate through symmetric division in which
one cell gives rise to identical daughter cells, followed by the neurogenesis
in which a subset of cells becomes restricted to a neuronal or glial lineage
(Anderson, 2001;
Gotz and Huttner, 2005). These
cells undergo asymmetric cell division in which one cell is maintained as a
multipotent progenitor cell, while the other is fated to differentiate into a
neuron or glia within a few rounds of cell division. Mechanisms that underlie the neuroectoderm to progenitor NB transition in the CNS of flies and vertebrates have been difficult to identify, in part because the transitions are not well ordered in space and time. By contrast, we find and describe here, that the development of Drosophila medulla neurons is a process that can be precisely described because the transition from neuroepithelial (NE) cells to NBs progresses in a synchronized and ordered manner.
The Drosophila visual system is composed of the retina and the
optic lobe. The latter contains three optic ganglia: lamina, medulla and
lobula. During embryonic development, the optic lobe invaginates from a region
of head epidermis called optic lobe placode
(Green et al., 1993). The
optic lobe loses contact with the outer surface of the embryo and forms an
epithelial vesicle attached to the brain
(Green et al., 1993), and soon
after larval hatching, its cells start to proliferate and separate into an
outer optic anlagen (OOA) and an inner optic anlagen (IOA)
(Hofbauer and Campos-Ortega,
1990). Towards the end of the first instar, the OOA adopts a
crescent shape, with the opening of the crescent pointing posteriorly
(Nassif et al., 2003). The OOA
generates the outer medulla and the lamina neurons, while the IOA generates
the inner medulla, the lobula and the lobula plate neurons. The epithelial
part of the OOA is composed of a single layer of NE cells. During first and
second instar stages, NE cells of the OOA proliferate by symmetric cell
division. NE cells differentiate into medulla NBs and lamina precursor cells
at the medial and the lateral edge, respectively
(Fig. 1A-C). Medulla NBs divide
asymmetrically along apico-basal axis and produce GMCs, which divide again and
become medulla neurons (Fig.
1C) (Egger et al.,
2007; Nassif et al.,
2003; Toriya et al.,
2006).
The mechanisms underlying neurogenesis have been most intensely studied in
the development of external sense organs and embryonic CNS of
Drosophila. In these systems, NBs are induced from among NE cells in
a `proneural cluster' that express `proneural genes' such as atonal,
achaete (ac), scute (sc) and lethal of
scute [l(1)sc] (Cabrera et
al., 1987; Jarman et al.,
1993; Jarman et al.,
1994; Martin-Bermudo et al.,
1991; Skeath and Carroll,
1992). These proneural genes encode basic helix-loop-helix (bHLH)
transcription factors that dimerize with another bHLH protein Daughterless
(Da) (Jarman et al., 1993;
Murre et al., 1989a;
Murre et al., 1989b;
Villares and Cabrera, 1987).
Single or several NBs are selected from each cluster by the mechanism known as
lateral inhibition (Artavanis-Tsakonas and
Simpson, 1991; Hassan and
Vaessin, 1996). In contrast to the external sense organs and
embryonic CNS, the differentiation from NE cells to medulla NBs is well
ordered (Egger et al., 2007).
We found a `proneural wave' of differentiation starts from the medial edge of
the NE sheet and sweeps the optic lobe from medial to lateral during third
instar (L3) stage; l(1)sc is expressed transiently at the wave front
and plays an important role in differentiation of NBs.
|
), Upd2
(Gilbert et al., 2005;
Hombria et al., 2005) and Upd3
(Agaisse et al., 2003); the
transmembrane receptor Domeless (Dome)
(Brown et al., 2001;
Chen et al., 2002); the JAK
homolog Hopscotch (Hop) (Binari and
Perrimon, 1994); and the STAT homolog Stat92E
(Hou et al., 1996;
Yan et al., 1996). JAK/STAT
signaling is involved in many developmental processes, including segmentation
in embryogenesis, eye morphogenesis, hematopoiesis and stem cell maintenance
(Arbouzova and Zeidler, 2006;
Luo and Dearolf, 2001;
Zeidler et al., 2000). Here,
we report a novel mechanism underlying NB (neural progenitor) formation and
discuss its role in establishing a precise topographic map in the visual
system. |
MATERIALS AND METHODS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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).
ap-lacZ is a P element enhancer trap insertion just 5' of the
apterous gene and expressed in 
50 % of medulla neurons
(Cohen et al., 1992).
upd-Gal4 is an enhancer trap line of upd
(Halder et al., 1995;
Tsai and Sun, 2004) and its
expression was visualized by crossing with UAS-GFP.nls flies.
10xSTAT-GFP is an in vivo detector that reflects the activation of
JAK/STAT signal (Bach et al.,
2007). UAS-l(1)sc was described previously
(Carmena et al., 1995).
UAS-l(1)sc was overexpressed by crossing with NP6099 driver
(Hayashi et al., 2002;
Yoshida et al., 2005).
Overexpression clones of UAS-upd
(Zeidler et al., 1999) and
UAS-hopTum-l (Harrison
et al., 1995) were induced by hs-flp; AyGal4 flies
(Ito et al., 1997).
eya1 is a mutant allele of eyes absent described
by Bonini et al. (Bonini et al.,
1993). Deficiency chromosome of Df(1)260-1, Df(1)sc10-1,
Df(1)sc19 or Df(1)ase1 was recombined onto FRT19A.
These clones were induced by NP7340
(Hayashi et al., 2002).
UAS-flp. da10 is an amorphic allele of the da
mutant (Caudy et al., 1988).
Clones of da10 were induced by NP6099 UAS-flp.
hop2 is a null allele of hop
(Perrimon and Mahowald, 1986).
Stat92E85C9 is a strong hypomorphic allele of
Stat92E (Silver and Montell,
2001) and Stat92E6346 is a putative null
allele of Stat92E (Hou et al.,
1996). Stat92EF is a temperature-sensitive
allele of Stat92E (Baksa et al.,
2002). Stat92E85C9/Sta92EF and
Stat92E 6346/Stat92EF flies were raised at
29°C. To assess the function of Stat92E, we generated clones in a
Minute back ground with hsflp; FRT82 ubi-GFP
M(3)w124 (Ferrus,
1975).
|
;
Takei et al., 2004). The
following antibodies were provided by the Developmental Studies Hybridoma Bank
(DSHB): mouse anti-Dac (mAbdac2-3, 1:1000), mouse anti-Arm (N2 7A1, 1:40) and
rat anti-Elav (7E8A10, 1:50). Rabbit anti-Tll (1:600) was provided by East
Asian Distribution Center for Segmentation Antibodies. We also used rat
anti-L(1)sc (1:800, A. Carmena), guinea pig anti-Dpn (1/1000, J. Skeath),
rabbit anti-Ase (1:2000, Y. N. Jan), rabbit anti-Dlg (1:1000, T. Uemura), goat
anti-Horseradish Peroxidase (HRP, 1:100, Accurate Chemical and Scientific),
rabbit anti-cleaved Caspase 3 (1:100, Cell Signaling Technology), mouse
anti-β-gal (1:250, Promega) and rabbit anti-β-gal (1:2000, Cappel).
Secondary antibodies (Jackson) were used at the following dilutions:
anti-mouse Cy3, 1:200; anti-mouse Cy5, 1:200; anti-mouse FITC, 1:200;
anti-guinea pig Cy3, 1:200; anti-guinea pig Cy5, 1:200; anti-rat Cy3, 1:200;
anti-rat Cy5, 1:200; anti-rabbit FITC, 1:200; anti-rabbit Cy5, 1:200;
anti-rabbit Alexa 546, 1:200 (Molecular Probes). Specimens were mounted with
vectashield mounting media (Vector) and viewed on a Zeiss LSM510 confocal
microscope.
In situ hybridization
In situ hybridization was performed as described previously
(Nagaso et al., 2001). DNA
template for the upd probe has been described previously
(Tsai and Sun, 2004).
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RESULTS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Medulla
neurons derive from NBs on the medial side of the NE sheet; lamina neurons
derive directly from the lateral side of the OOA without formation of NBs
(Fig. 1B-F)
(Nassif et al., 2003). Medulla
NBs are generated during L3 stages both by symmetric divisions of the OOA NE
cells and progressively from the medial edge
(Fig. 1G-J)
(Egger et al., 2007;
Nassif et al., 2003). NB
generation is synchronized, forming a one-cell wide band of newly
differentiated NBs to the inner slope of the U-shaped developing OOA. The NBs
divide asymmetrically with their division plane oriented perpendicular to the
surface and along the apico-basal axis; they produce medulla neurons basally
and expand the volume of the optic lobe
(Fig. 1C,F)
(Ceron et al., 2001;
Egger et al., 2007;
Toriya et al., 2006). As the
swath of NBs widens during maturation of the optic lobe, the expanse of NE
cells decreases (Fig. 1G-J). On
the lateral most side, NE cells receive Hedgehog (Hh) signals from innervating
R axons and differentiate into lamina neurons
(Fig. 1C,F)
(Huang and Kunes, 1996;
Huang and Kunes, 1998).
|
;
Jimenez and Campos-Ortega,
1990; Martin-Bermudo et al.,
1991) is transiently expressed in a narrow band of 1-2 cells at
the medial edge of the NE sheet (Fig.
2A-G). This band precedes NB formation and moves laterally
throughout the L3 period. The expression pattern of L(1)sc led us to test the
idea that L(1)sc makes NE cells competent to differentiate into medulla NBs.
We overexpressed l(1)sc in most of the NE cells during the stages
when medulla neurogenesis begins, and observed that, at early stages, the
number of Deadpan (Dpn)-expressing cells on the surface of the optic lobe
increased; at later stages, only medulla neurons were observed and lamina was
not formed (Fig. 2K-M; 100%;
n=20, compare with Fig.
2H-J, see also Fig. S1 in the supplementary material). These
results suggest that L(1)sc activity is sufficient to induce NBs, and the
medulla and lamina neuron precursors derive from the limited number of cells
in a common primordium. As L(1)sc-expressing cells lead a front that sweeps
across the optic lobe and induces differentiation of NBs, we refer to the band
of L(1)sc-expressing cells as the proneuroal wave
(Fig. 2G). The proneural wave
converts all NE cells to NBs in an ordered manner from the medial side. This
program contrasts with the neurogenesis of the Drosophila sense
organs or embryonic CNS in which only one or several NBs are selected from the
NE cells.
|
). In
clones of cells mutant for da10, an amorphic allele of
da, expression of Dpn was strongly reduced
(Fig. 3D; n=18). As
Dpn often remained in the medial cells of the clones, we infer that Dpn
expression is delayed in mutant cells. However, L(1)sc expression was not
affected in mutant cells (Fig.
3E,K; n=13). We conclude that proneural function is
required to time NB differentiation but not for progression of the proneural
wave. This result also suggests that the progression of the proneural wave is
independent of NB differentiation.
In order to assess the requirement for other proneural genes, we used
deficiency chromosomes that delete various regions of the
achaete-scute complex (AS-C;
Fig. 3F). The AS-C
contains four bHLH proneural genes: ac, sc, l(1)sc and
asense (ase). In wild type, Ac expression was not detected;
both NE cells and NBs express Sc (Egger et
al., 2007) and Ase expression was detected in NBs
(Fig. 3A-C). Mutant clones
deficient for all the proneural genes [Df(1)260-1
(Hinz et al., 1994)] caused
the delay in Dpn expression by 4-6 rows of cells, which is indistinguishable
from the da mutant clones, suggesting that only these four proneural
genes are crucial for the proneural function in the optic lobe
(Fig. 3G,K; n=29). As
clones deficient for both ac and sc [Df(1)sc10-1
(Campuzano et al., 1985)] did
not affect Dpn expression (Fig.
3H; n=10), we conclude that ac and sc
are not essential for NB differentiation. However, Dpn expression was delayed
by 1-2 rows of cell in clones deficient for ac, sc and
l(1)sc [Df(1)sc19
(Carmena et al., 1995)],
suggesting that l(1)sc is required for the timely onset of NB
formation (Fig. 3I,K;
n=36). Ase expression was not affected in these clones (data not
shown). Mutant clones deficient for ase
(Brand et al., 1993) initiated
Dpn expression normally (Fig.
3J; n=19), suggesting that ase is required for
timing of the normal onset of NB formation when l(1)sc is impaired.
Sc might also have a redundant function but appropriate deficiency chromosomes
are not available at present to unambiguously study the role of Sc. We also
examined whether the onset of NB formation is regulated by inputs from the
retinal axons because lamina development depends on arriving retinal axons (R
axons) (Selleck and Steller,
1991). The `eyeless' mutant, eya1
(Bonini et al., 1993), did not
affect L(1)sc expression or medulla NB differentiation, suggesting that
medulla neurogenesis is independent of R axon projection at least at this
early phase (see Fig. S2A,B in the supplementary material). However, the
medulla neuropil of this mutant was poorly organized in the later pupal stage
partly because of excess cell death (see Fig. S2C,D in the supplementary
material).
JAK/STAT signal is activated in NE cells
We next searched for genes that regulate proneural wave progression and
determined that upd is expressed in NE cells
(Fig. 4). Analysis of
upd-Gal4 (Halder et al.,
1995; Tsai and Sun,
2004) suggests that the pattern of upd expression is
dynamic. In the early L3 stage, upd-Gal4 is expressed in some NE
cells that express high levels of Armadillo (Arm)
(Fig. 4A)
(Hayden et al., 2007).
upd-Gal4 expression was restricted to the lateral side of the NE in
mid L3 (Fig. 4B) and was in the
lamina neuron precursors in late L3 (Fig.
4C, see Fig. S3A in the supplementary material). In the early to
mid L3, expression pattern of upd mRNA was similar to that of
upd-Gal4 (see Fig. S3B,C in the supplementary material). But in late
L3, upd mRNA was specifically expressed in the lamina furrow that is
located at the most lateral NE cells (see Fig. S3D,E in the supplementary
material). The different patterns observed in the enhancer trap expression and
mRNA distribution might be caused by perdurance of the Gal4 and/or GFP
reporter protein (Tsai and Sun,
2004).
To determine where the JAK/STAT signal is activated in the optic lobe, the
expression of a 10xSTAT-GFP reporter construct
(Bach et al., 2007) was
examined. GFP fluorescence was observed from early L3
(Fig. 4D), and was detected in
the lateral side of the NE cells in mid L3
(Fig. 4E). In late L3, the GFP
fluorescence was weak in the NE cells and stronger in the lamina
(Fig. 4F). These results
suggest that JAK/STAT signaling is activated in the NE cells at least in early
to mid L3, and that it is low medially and higher in the lateral NE cells
(Fig. 4B,E).
|
), both NE cells and NBs were found to express
high levels of Arm and Dpn (Fig.
5A,B; 100%; n=9). In the wild type, they are co-expressed
only in cells at the transition from NE cells to NBs. Late L3 mutant optic
lobes were smaller, had few NBs, the number of neurons was fewer and lamina
neurons were absent (Fig. 5C,D;
100%; n=20). We infer that NBs developed prematurely in the
hop2 mutant and that in the absence of the JAK/STAT
signal, there was insufficient proliferation of the NE cells prior to
transition to the NB fate. Similar phenotypes were observed in
Stat92E85C9/Stat92EF or
Stat92E6346/Stat92EF loss-of-function mutants
(see Fig. S4 in the supplementary material and data not shown). To examine
whether Elav-expressing neurons observed in hop2 mutant
were differentiated medulla neurons, optic lobes are stained by
ap-lacZ (Fig. 5E,F).
Neurons in hop2 mutant expressed ap-lacZ, which
indicates that though the number of NBs in hop2 was fewer
than wild-type flies, NBs in the mutant optic lobe produce differentiated
medulla neurons (Fig. 5F; 100%;
n=15).
To further investigate the role of JAK/STAT signaling, Stat92E
mutant clones were generated. Near clones of Stat92E85C9,
which is a strong hypomorphic allele of Stat92E
(Silver and Montell, 2001),
both L(1)sc and Dpn were expressed in more lateral cells than in surrounding
Stat92E85C9/+ cells
(Fig. 6A,H; n=29),
expression of Ase was present at more lateral locations, and ectopic Elav
expression was observed within and near Stat92E6346
(putative null allele of Stat92E)
(Hou et al., 1996) clones
(Fig. 6B; n=21). These
results suggest that loss of Stat92E function leads to faster progression of
proneural wave and earlier initiation of medulla differentiation.
Interestingly, these phenotypes were not cell-autonomous. Ectopic expression
of L(1)sc was observed not only in the mutant cells but, in some cases, in
adjacent Stat92E85C9/+ cells as well
(Fig. 6A', arrowheads).
When Stat92E85C9 clones were extended into the putative
lamina region, Dac-expressing lamina precursors disappeared and Dpn-expressing
medulla NBs occupied the region (Fig.
6C; n=27). This suggests that the number of lamina
neurons and medulla neurons is balanced by the JAK/STAT signal.
|
). Clones in the NE cells were associated with more medial
expression of L(1)sc and delayed expression of Dpn
(Fig. 6D,H; n=17).
Cells that did not express Dpn expressed high Arm, indicating that they
remained in an undifferentiated NE state
(Fig. 6E; n=20). When
upd was overexpressed (as above), a similar phenotype was observed
(Fig. 6F,G; n=20 for
F; n=10 for G). These results are consistent with the expectation
that Upd acts as an extracellular activator of the JAK/STAT pathway. Note that
the phenotypes were not cell autonomous and the proneural wave was continuous,
even when it extended more medially (with elevated JAK/STAT signaling) or
laterally (with decreased signaling). These results suggest that JAK/STAT
signaling negatively regulates the progression of the proneural wave and that
it does not directly regulate expression of the proneural genes
(Fig. 6I). The alteration in
proneural wave progression described here cannot be attributed solely to
growth defects because any differences in proneural wave progression were
associated with slowly growing Minute clones (see Fig. S5 in the
supplementary material).
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|
DISCUSSION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Proneural wave sweeps from the medial to lateral optic lobe and induces medullar NB differentiation
NE cells are programmed to differentiate into NBs from the medial edge of
the developing optic lobe. The wave of differentiation progresses
synchronously in a row of cells from medial to lateral optic lobe sweeping
across the entire NE sheet; it is preceded by the transient expression of the
proneural gene l(1)sc. As the NBs at the medial edge are oldest and
the more lateral ones are youngest, developmental process of medulla neurons
can be viewed as an array of progressively aged cells across optic lobe
mediolaterally. This contrasts with NB formation in the embryonic CNS in which
a small number of cells are selected from NE cells to become NBs, leaving the
majority of NE cells to develop into non-neural cells. The optic lobe
proneural wave is reminiscent of the morphogenetic furrow that moves across
the developing eye imaginal disc. The morphogenetic furrow is the site where
differentiation from neuroepithelium to photoreceptor neurons is initiated
(Ready et al., 1976). The
progression is driven by the secreted Hh expressed in the differentiated
photoreceptor cells (Heberlein and Moses,
1995; Heberlein et al.,
1993; Ma et al.,
1993). By contrast, the proneural wave still progresses even when
NB differentiation is impaired, suggesting that its progression is not driven
by a factor emanating from differentiated NBs. We failed to observe
progression-defective phenotypes when Hh or Decapentaplegic (Dpp) signaling
was reduced (T.T., unpublished). We favor the model that the proneural wave
progression is driven by an intrinsic mechanism such as a segmentation clock
and is negatively regulated by JAK/STAT pathway
(Fig. 7). As the JAK/STAT
ligand Upd is expressed only by the most lateral NE cells, proliferation of
the NE cells moves the source of ligand laterally and as a consequence
releases more medial NE cells from negative regulation and allows the
proneural wave to progress laterally. Alternatively, distribution of the Upd
ligand and/or the response to Upd changes as the NE cells age as graded
10xSTAT-GFP activities are more prominent in the early stage. Non-autonomous
action of JAK/STAT signal indicates that it does not directly regulate L(1)sc
expression and there are second signal(s) that regulate the expression of
L(1)sc under the control of JAK/STAT signal.
Three out of the four AS-C genes [sc, l(1)sc and
ase] are expressed during medulla neurogenesis. l(1)sc is
expressed in NE cells and ase in NBs, while sc is expressed
both in NE cells and NBs (Egger et al.,
2007). Deleting all AS-C genes causes as significant
delay as da in NB formation but does not completely eliminate NB
formation, suggesting that Da-dependent proneural gene activities are required
for timely onset of NB formation. Mutation for sc or ase
alone does not affect NB formation, but the simultaneous deletion of
sc and l(1)sc causes the delay in NB formation and the
additional deletion of ase further delays NB formation. ase
expression is not altered in the absence of l(1)sc and
l(1)sc is not altered in the absence of ase, indicating that
l(1)sc and ase both contribute to the differentiation from
NE cells to NBs. Although the contribution of Sc cannot be formally excluded,
the highly specific expression pattern led us to infer that L(1)sc plays a
major role in the proneural wave.
JAK/STAT signaling in stem cell maintenance
JAK/STAT signaling is known to regulate stem cell maintenance in the adult
germline of Drosophila (Arbouzova
and Zeidler, 2006; Fuller and
Spradling, 2007). In the male testis, germline stem cells (GSCs)
attach to a cluster of somatic support cells at the tip (hub) of the testis.
When a GSC divides, the daughter retaining contact with the hub maintains
self-renewing GSC identity, while the other daughter differentiates into
gonialblast. Upd is specifically expressed in the hub cells and activates
JAK/STAT signal in the GSCs to maintain stem cell state
(Kiger et al., 2001;
Tulina and Matunis, 2001). In
the female ovary, JAK/STAT signaling is required in the somatic escort stem
cells whose daughters encase developing cysts
(Decotto and Spradling, 2005).
Here, we show that in the optic lobe development, JAK/STAT signaling maintains
NE cells in an undifferentiated state. We suggest that a common mechanism
operates in both these developmental systems. Loss of Hop or Stat92E function
decreases number of stem cells and ectopic expression of Upd results in over
proliferation of undifferentiated cells. The cell fate may be determined by
the distance of the cells from the source of ligand; the cells farther from
the source commence to differentiate.
In the vertebrate CNS, NE cells first proliferate by symmetric cell
divisions and differentiate into neurons and glia in later developmental
stages (Anderson, 2001;
Gotz and Huttner, 2005;
McKay, 1997). JAK/STAT
signaling has been implicated in maintenance of neural precursor cells
(Yoshimatsu et al., 2006), but
there is no clear evidence that those cells are in the same developmental
stage as we describe here for Drosophila. Further study of JAK/STAT
signaling will reveal whether a common mechanism underlies stem cell
development in both Drosophila and vertebrates, and should give new
insights into vertebrate CNS neurogenesis.
Retinotopic map regulated by JAK/STAT signal
Development of a precise topographic map (retinotopic map) in
Drosophila is known to involve regulation of lamina neuron
development with respect to the incoming R axons
(Selleck and Steller, 1991).
The lateral NE sheet is continuous with a groove called the lamina furrow
where NE cells are arrested at G1/S phase
(Fig. 1C)
(Selleck et al., 1992). The
arriving R axons deliver Hh and liberate the arrested NE cells to proliferate
and develop into lamina neuron precursors
(Fig. 1C)
(Huang and Kunes, 1996;
Huang and Kunes, 1998). And,
thus, R axons can induce the development of their synaptic partners in their
vicinity to balance the number of R axonal termini and lamina neurons.
However, medulla development does not depend on inputs from the R axons in the
early phase. As we have shown here, both lamina and medulla neurons are
derived from the continuous NE sheet. Large clones of cells mutant for the
JAK/STAT signaling cause immature proliferation of medulla NBs at the expense
of lamina neurons, suggesting that the number of NE cells serves as the
limiting factor to generate precursors for lamina and medulla neurons. Thus,
the number of medulla neurons is roughly regulated at the level of NBs whose
generation might be balanced indirectly with the number of lamina neurons
through regulating proneural wave progression by JAK/STAT signaling. JAK/STAT
signaling therefore plays an important role in the formation of a precise
retinotopic map in the visual center.
Supplementary material
Supplementary material for this article is available at
http://dev.biologists.org/cgi/content/full/135/8/1471/DC1
|
ACKNOWLEDGMENTS |
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|
Footnotes |
|---|
Present address: Max-Planck Institute of Molecular Cell Biology and
Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany
Present address: Frontier Science Organization, Kanazawa University 13-1
Takaramachi, Kanazawa, Ishikawa 920-8641, Japan
|
REFERENCES |
|---|
|
TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Agaisse, H., Petersen, U. M., Boutros, M., Mathey-Prevot, B. and Perrimon, N. (2003). Signaling role of hemocytes in Drosophila JAK/STAT-dependent response to septic injury. Dev. Cell 5,441 -450.[CrossRef][Medline]
Anderson, D. J. (2001). Stem cells and pattern formation in the nervous system: the possible versus the actual. Neuron 30,19 -35.[CrossRef][Medline]
Arbouzova, N. I. and Zeidler, M. P. (2006).
JAK/STAT signalling in Drosophila: insights into conserved regulatory and
cellular functions. Development
133,2605
-2616.
Artavanis-Tsakonas, S. and Simpson, P. (1991). Choosing a cell fate: a view from the Notch locus. Trends Genet. 7,403 -408.[Medline]
Bach, E. A., Ekas, L. A., Ayala-Camargo, A., Flaherty, M. S., Lee, H., Perrimon, N. and Baeg, G. H. (2007). GFP reporters detect the activation of the Drosophila JAK/STAT pathway in vivo. Gene Expr. Patterns 7,323 -331.[CrossRef][Medline]
Baksa, K., Parke, T., Dobens, L. L. and Dearolf, C. R. (2002). The Drosophila STAT protein, stat92E, regulates follicle cell differentiation during oogenesis. Dev. Biol. 243,166 -175.[CrossRef][Medline]
Binari, R. and Perrimon, N. (1994).
Stripe-specific regulation of pair-rule genes by hopscotch, a putative Jak
family tyrosine kinase in Drosophila. Genes Dev.
8, 300-312.
Bonini, N. M., Leiserson, W. M. and Benzer, S. (1993). The eyes absent gene: genetic control of cell survival and differentiation in the developing Drosophila eye. Cell 72,379 -395.[CrossRef][Medline]
Brand, M., Jarman, A. P., Jan, L. Y. and Jan, Y. N. (1993). asense is a Drosophila neural precursor gene and is capable of initiating sense organ formation. Development 119,1 -17.[Abstract]
Brown, S., Hu, N. and Hombria, J. C. (2001). Identification of the first invertebrate interleukin JAK/STAT receptor, the Drosophila gene domeless. Curr. Biol. 11,1700 -1705.[CrossRef][Medline]
Cabrera, C. V., Martinez-Arias, A. and Bate, M. (1987). The expression of three members of the achaete-scute gene complex correlates with neuroblast segregation in Drosophila. Cell 50,425 -433.[CrossRef][Medline]
Campos-Ortega, J. A. (1993). Early neurogenesis in Drosophila melanogaster. In The Development of Drosophila melanogaster (ed. M. Bate and A. Martinez-Arias), pp.1091 -1130. Cold Spring Harbor: Cold Spring Harbor Laboratory Press.
Campuzano, S., Carramolino, L., Cabrera, C. V., Ruiz-Gomez, M., Villares, R., Boronat, A. and Modolell, J. (1985). Molecular genetics of the achaete-scute gene complex of D. melanogaster. Cell 40,327 -338.[CrossRef][Medline]
Carmena, A., Bate, M. and Jimenez, F. (1995).
Lethal of scute, a proneural gene, participates in the specification of muscle
progenitors during Drosophila embryogenesis. Genes
Dev. 9,2373
-2383.
Caudy, M., Vassin, H., Brand, M., Tuma, R., Jan, L. Y. and Jan, Y. N. (1988). daughterless, a Drosophila gene essential for both neurogenesis and sex determination, has sequence similarities to myc and the achaete-scute complex. Cell 55,1061 -1067.[CrossRef][Medline]
Ceron, J., Gonzalez, C. and Tejedor, F. J. (2001). Patterns of cell division and expression of asymmetric cell fate determinants in postembryonic neuroblast lineages of Drosophila. Dev. Biol. 230,125 -138.[CrossRef][Medline]
Chen, H. W., Chen, X., Oh, S. W., Marinissen, M. J., Gutkind, J.
S. and Hou, S. X. (2002). mom identifies a receptor for the
Drosophila JAK/STAT signal transduction pathway and encodes a protein
distantly related to the mammalian cytokine receptor family. Genes
Dev. 16,388
-398.
Cohen, B., McGuffin, M. E., Pfeifle, C., Segal, D. and Cohen, S.
M. (1992). apterous, a gene required for imaginal disc
development in Drosophila encodes a member of the LIM family of developmental
regulatory proteins. Genes Dev.
6, 715-729.
Decotto, E. and Spradling, A. C. (2005). The Drosophila ovarian and testis stem cell niches: similar somatic stem cells and signals. Dev. Cell 9,501 -510.[CrossRef][Medline]
Egger, B., Boone, J. Q., Stevens, N. R., Brand, A. H. and Doe, C. Q. (2007). Regulation of spindle orientation and neural stem cell fate in the Drosophila optic lobe. Neural Dev. 2,1 .[CrossRef]
Ferrus, A. (1975). Parameters of mitotic
recombination in minute mutants of Drosophila melanogaster.
Genetics 79,589
-599.
Fuerstenberg, S., Broadus, J. and Doe, C. Q. (1998). Asymmetry and cell fate in the Drosophila embryonic CNS. Int. J. Dev. Biol. 42,379 -383.[Medline]
Fuller, M. T. and Spradling, A. C. (2007). Male
and female Drosophila germline stem cells: two versions of immortality.
Science 316,402
-404.
Gilbert, M. M., Weaver, B. K., Gergen, J. P. and Reich, N. C. (2005). A novel functional activator of the Drosophila JAK/STAT pathway, unpaired2, is revealed by an in vivo reporter of pathway activation. Mech. Dev. 122,939 -948.[CrossRef][Medline]
Goodman, C. S. and Doe, C. Q. (1993). Embryonic development of the Drosophila central nervous system. In The Development of Drosophila melanogaster (ed. M. Bate and A. Martinez-Arias), pp. 1131-1206. Cold Spring Harbor: Cold Spring Harbor Laboratory Press.
Gotz, M. and Huttner, W. B. (2005). The cell biology of neurogenesis. Nat. Rev. Mol. Cell Biol. 6, 777-788.[CrossRef][Medline]
Green, P., Hartenstein, A. Y. and Hartenstein, V. (1993). The embryonic development of the Drosophila visual system. Cell Tissue Res. 273,583 -598.[CrossRef][Medline]
Halder, G., Callaerts, P. and Gehring, W. J.
(1995). Induction of ectopic eyes by targeted expression of the
eyeless gene in Drosophila. Science
267,1788
-1792.
Harrison, D. A., Binari, R., Nahreini, T. S., Gilman, M. and Perrimon, N. (1995). Activation of a Drosophila Janus kinase (JAK) causes hematopoietic neoplasia and developmental defects. EMBO J. 14,2857 -2865.[Medline]
Harrison, D. A., McCoon, P. E., Binari, R., Gilman, M. and
Perrimon, N. (1998). Drosophila unpaired encodes a secreted
protein that activates the JAK signaling pathway. Genes
Dev. 12,3252
-3263.
Hassan, B. and Vaessin, H. (1996). Regulatory interactions during early neurogenesis in Drosophila. Dev. Genet. 18,18 -27.[CrossRef][Medline]
Hayashi, S., Ito, K., Sado, Y., Taniguchi, M., Akimoto, A., Takeuchi, H., Aigaki, T., Matsuzaki, F., Nakagoshi, H., Tanimura, T. et al. (2002). GETDB, a database compiling expression patterns and molecular locations of a collection of Gal4 enhancer traps. Genesis 34,58 -61.[CrossRef][Medline]
Hayden, M. A., Akong, K. and Peifer, M. (2007). Novel roles for APC family members and Wingless/Wnt signaling during Drosophila brain development. Dev. Biol. 305,358 -376.[CrossRef][Medline]
Heberlein, U. and Moses, K. (1995). Mechanisms of Drosophila retinal morphogenesis: the virtues of being progressive. Cell 81,987 -990.[CrossRef][Medline]
Heberlein, U., Wolff, T. and Rubin, G. M. (1993). The TGF beta homolog dpp and the segment polarity gene hedgehog are required for propagation of a morphogenetic wave in the Drosophila retina. Cell 75,913 -926.[CrossRef][Medline]
Hinz, U., Giebel, B. and Campos-Ortega, J. A. (1994). The basic-helix-loop-helix domain of Drosophila lethal of scute protein is sufficient for proneural function and activates neurogenic genes. Cell 76,77 -87.[CrossRef][Medline]
Hofbauer, A. and Campos-Ortega, J. A. (1990). Proliferation pattern and early differentiation of the optic lobes in Drosophila melanogaster. Roux's Arch. Dev. Biol. 198,264 -274.[CrossRef]
Hombria, J. C., Brown, S., Hader, S. and Zeidler, M. P. (2005). Characterisation of Upd2, a Drosophila JAK/STAT pathway ligand. Dev. Biol. 288,420 -433.[CrossRef][Medline]
Hou, X. S., Melnick, M. B. and Perrimon, N. (1996). Marelle acts downstream of the Drosophila HOP/JAK kinase and encodes a protein similar to the mammalian STATs. Cell 84,411 -419.[CrossRef][Medline]
Huang, Z. and Kunes, S. (1996). Hedgehog, transmitted along retinal axons, triggers neurogenesis in the developing visual centers of the Drosophila brain. Cell 86,411 -422.[CrossRef][Medline]
Huang, Z. and Kunes, S. (1998). Signals transmitted along retinal axons in Drosophila: Hedgehog signal reception and the cell circuitry of lamina cartridge assembly. Development 125,3753 -3764.[Abstract]
Ito, K., Awano, W., Suzuki, K., Hiromi, Y. and Yamamoto, D. (1997). The Drosophila mushroom body is a quadruple structure of clonal units each of which contains a virtually identical set of neurones and glial cells. Development 124,761 -771.[Abstract]
Jarman, A. P., Grau, Y., Jan, L. Y. and Jan, Y. N. (1993). atonal is a proneural gene that directs chordotonal organ formation in the Drosophila peripheral nervous system. Cell 73,1307 -1321.[CrossRef][Medline]
Jarman, A. P., Grell, E. H., Ackerman, L., Jan, L. Y. and Jan, Y. N. (1994). Atonal is the proneural gene for Drosophila photoreceptors. Nature 369,398 -400.[CrossRef][Medline]
Jimenez, F. and Campos-Ortega, J. A. (1990). Defective neuroblast commitment in mutants of the achaete-scute complex and adjacent genes of D. melanogaster. Neuron 5, 81-89.[CrossRef][Medline]
Kiger, A. A., Jones, D. L., Schulz, C., Rogers, M. B. and
Fuller, M. T. (2001). Stem cell self-renewal specified by
JAK-STAT activation in response to a support cell cue.
Science 294,2542
-2545.
Luo, H. and Dearolf, C. R. (2001). The JAK/STAT pathway and Drosophila development. BioEssays 23,1138 -1147.[CrossRef][Medline]
Ma, C., Zhou, Y., Beachy, P. A. and Moses, K. (1993). The segment polarity gene hedgehog is required for progression of the morphogenetic furrow in the developing Drosophila eye. Cell 75,927 -938.[CrossRef][Medline]
Martin-Bermudo, M. D., Martinez, C., Rodriguez, A. and Jimenez, F. (1991). Distribution and function of the lethal of scute gene product during early neurogenesis in Drosophila. Development 113,445 -454.[Abstract]
McKay, R. (1997). Stem cells in the central
nervous system. Science
276, 66-71.
Murre, C., McCaw, P. S. and Baltimore, D. (1989a). A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, MyoD, and myc proteins. Cell 56,777 -783.[CrossRef][Medline]
Murre, C., McCaw, P. S., Vaessin, H., Caudy, M., Jan, L. Y., Jan, Y. N., Cabrera, C. V., Buskin, J. N., Hauschka, S. D., Lassar, A. B. et al. (1989b). Interactions between heterologous helix-loop-helix proteins generate complexes that bind specifically to a common DNA sequence. Cell 58,537 -544.[CrossRef][Medline]
Nagaso, H., Murata, T., Day, N. and Yokoyama, K. K.
(2001). Simultaneous detection of RNA and protein by in situ
hybridization and immunological staining. J. Histochem.
Cytochem. 49,1177
-1182.
Nassif, C., Noveen, A. and Hartenstein, V. (2003). Early development of the Drosophila brain: III. The pattern of neuropile founder tracts during the larval period. J. Comp. Neurol. 455,417 -434.[CrossRef][Medline]
Perrimon, N. and Mahowald, A. P. (1986). l(1)hopscotch, a larval-pupal zygotic lethal with a specific maternal effect on segmentation in Drosophila. Dev. Biol. 118, 28-41.[CrossRef][Medline]
Ready, D. F., Hanson, T. E. and Benzer, S. (1976). Development of the Drosophila retina, a neurocrystalline lattice. Dev. Biol. 53,217 -240.[CrossRef][Medline]
Selleck, S. B. and Steller, H. (1991). The influence of retinal innervation on neurogenesis in the first optic ganglion of Drosophila. Neuron 6,83 -99.[CrossRef][Medline]
Selleck, S. B., Gonzalez, C., Glover, D. M. and White, K. (1992). Regulation of the G1-S transition in postembryonic neuronal precursors by axon ingrowth. Nature 355,253 -255.[CrossRef][Medline]
Silver, D. L. and Montell, D. J. (2001). Paracrine signaling through the JAK/STAT pathway activates invasive behavior of ovarian epithelial cells in Drosophila. Cell 107,831 -841.[CrossRef][Medline]
Skeath, J. B. and Carroll, S. B. (1992). Regulation of proneural gene expression and cell fate during neuroblast segregation in the Drosophila embryo. Development 114,939 -946.[Abstract]
Takei, Y., Ozawa, Y., Sato, M., Watanabe, A. and Tabata, T.
(2004). Three Drosophila EXT genes shape morphogen gradients
through synthesis of heparan sulfate proteoglycans.
Development 131,73
-82.
Tanimoto, H., Itoh, S., ten Dijke, P. and Tabata, T. (2000). Hedgehog creates a gradient of DPP activity in Drosophila wing imaginal discs. Mol. Cell 5, 59-71.[CrossRef][Medline]
Toriya, M., Tokunaga, A., Sawamoto, K., Nakao, K. and Okano, H. (2006). Distinct functions of human numb isoforms revealed by misexpression in the neural stem cell lineage in the Drosophila larval brain. Dev. Neurosci. 28,142 -155.[CrossRef][Medline]
Tsai, Y. C. and Sun, Y. H. (2004). Long-range effect of upd, a ligand for Jak/STAT pathway, on cell cycle in Drosophila eye development. Genesis 39,141 -153.[CrossRef][Medline]
Tulina, N. and Matunis, E. (2001). Control of
stem cell self-renewal in Drosophila spermatogenesis by JAK-STAT signaling.
Science 294,2546
-2549.
Villares, R. and Cabrera, C. V. (1987). The achaete-scute gene complex of D. melanogaster: conserved domains in a subset of genes required for neurogenesis and their homology to myc. Cell 50,415 -424.[CrossRef][Medline]
Yan, R., Small, S., Desplan, C., Dearolf, C. R. and Darnell, J. E., Jr (1996). Identification of a Stat gene that functions in Drosophila development. Cell 84,421 -430.[CrossRef][Medline]
Yoshida, S., Soustelle, L., Giangrande, A., Umetsu, D.,
Murakami, S., Yasugi, T., Awasaki, T., Ito, K., Sato, M. and Tabata, T.
(2005). DPP signaling controls development of the lamina glia
required for retinal axon targeting in the visual system of Drosophila.
Development 132,4587
-4598.
Yoshimatsu, T., Kawaguchi, D., Oishi, K., Takeda, K., Akira, S.,
Masuyama, N. and Gotoh, Y. (2006). Non-cell-autonomous action
of STAT3 in maintenance of neural precursor cells in the mouse neocortex.
Development 133,2553
-2563.
Yu, F., Kuo, C. T. and Jan, Y. N. (2006). Drosophila neuroblast asymmetric cell division: recent advances and implications for stem cell biology. Neuron 51, 13-20.[CrossRef][Medline]
Zeidler, M. P., Perrimon, N. and Strutt, D. I.
(1999). Polarity determination in the Drosophila eye: a novel
role for unpaired and JAK/STAT signaling. Genes Dev.
13,1342
-1353.
Zeidler, M. P., Bach, E. A. and Perrimon, N. (2000). The roles of the Drosophila JAK/STAT pathway. Oncogene 19,2598 -2606.[CrossRef][Medline]
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