1 Department of Molecular and Cellular Biology, Baylor College of Medicine, One
Baylor Plaza, Houston, TX 77030, USA
2 Program in Developmental Biology, Baylor College of Medicine, One Baylor
Plaza, Houston, TX 77030, USA
3 Department of Ophthalmology, Baylor College of Medicine, One Baylor Plaza,
Houston, TX 77030, USA
* Author for correspondence (e-mail: kchoi{at}bcm.tmc.edu)
Accepted 27 August 2004
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SUMMARY |
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Key words: Bar homeodomain protein, Atonal, Hedgehog, Retinal neurogenesis, Drosophila eye
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Introduction |
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The adult eye consists of about 800 unit eyes or ommatidia, each of which
harbors eight photoreceptor (R1-R8) cells
(Ready et al., 1976;
Wolff and Ready, 1993
).
Retinal neurogenesis takes place in a specific region of the developing eye
called the morphogenetic furrow, which is generated at the posterior margin of
the disc and progresses anteriorly
(Heberlein et al., 1993
;
Ma et al., 1993
;
Dominguez and Hafen, 1997
;
Borod and Heberlein, 1998
;
Greenwood and Struhl, 1999
;
Curtiss and Mlodzik, 2000
).
The bHLH transcription factor Ato plays a key role in the furrow to initiate
retinal neurogenesis (Jarman et al.,
1994
). Ato expression is dynamically regulated in the furrow
(Frankfort and Mardon, 2002
).
Ato is expressed as a stripe pattern across the disc in the anterior region of
the furrow (stage 1). Posterior to the stripe, Ato expression is restricted to
about 20 cell groups called intermediate groups followed by R8 equivalence
groups of two or three cells (stages 2/3). Finally, Ato expression is
restricted to evenly spaced single cells that become R8 founder neurons (stage
4). After R8 selection, Ato-positive (Ato+) R8 cells sequentially
recruit other photoreceptors from surrounding undifferentiated cells to form
clusters of eight photoreceptors (Ready et
al., 1976
; Wolff and Ready,
1993
).
Interestingly, positions of cell nuclei in the developing eye imaginal disc
are dynamically regulated during retinal differentiation
(Wolff and Ready, 1993). Prior
to the furrow initiation or in undifferentiated region anterior to the furrow,
nuclei of cells are randomly distributed throughout the depth of the disc
epithelium. As the furrow progresses anteriorly, nuclei of the cells within
the furrow sink and stay in the basal region of the disc. Posterior to the
furrow, nuclei of cells that become photoreceptor precursors migrate apically,
while those of undifferentiated cells stay in basal region of the disc,
resulting in the formation of two distinct layers of nuclei
(Fig. 1A). Consistent with this
nuclear migration during retinal differentiation, nuclear positions of
Ato-expressing cells near the furrow are also tightly regulated depending on
its expression stages. The nuclei of Ato-expressing cells locate basally
during stage 1 and 2 expression but migrate apically during stage 3 and remain
near the apical surface of the eye disc throughout stage 4 expression
(Frankfort and Mardon,
2002
).
|
Bar class homeodomain proteins are evolutionarily conserved and have been
implicated in cell-fate specification and neuronal differentiation in
Drosophila as well as other species
(Higashijima et al., 1992;
Jones et al., 1997
;
Saito et al., 1998
;
Bulfone et al., 2000
;
Patterson et al., 2000
;
Lim and Choi, 2003
;
Saba et al., 2003
;
Mo et al., 2004
;
Poggi et al., 2004
). A pair of
redundant Drosophila Bar proteins encoded by two adjacent genes
BarH1 and BarH2 (hereafter `Bar' for both) are
specifically expressed in the nuclei of R1/6 photoreceptor neurons and are
required for their differentiation (Fig.
1A) (Higashijima et al.,
1992
), although this requirement appears to be partial (J.L. and
K.-W.C., unpublished). Importantly, Bar shows a specific expression pattern in
the basal undifferentiated retinal precursor cells (hereafter `basal
undifferentiated cells') posterior to the furrow
(Fig. 1A). Intriguingly, the
anterior boundary of Bar expression in the basal undifferentiated cells is
juxtaposed to the posterior boundary of Ato expression in the furrow,
resulting in a complementary expression pattern across the eye disc along the
furrow (Fig. 1B) (Lim and Choi, 2003
). Loss of
Bar in the undifferentiated basal cells results in ectopic
ato gene expression and ectopic photoreceptor clusters, indicating
that Bar proteins are essential for transcriptional repression of ato
and thus for prevention of ectopic retinal neurogenesis posterior to the
furrow (Lim and Choi,
2003
).
Because Bar genes play an essential role in the negative control of ato proneural gene, the expression of Bar must be precisely regulated in coordination with the initiation and progression of retinal differentiation in the developing eye disc. Hence, the identification of signaling factors that regulate Bar expression in the basal undifferentiated cells is important to understand how the complementary expression domains of Ato and Bar proteins are established and maintained during eye morphogenesis.
We have addressed this question of Bar gene regulation and show that levels of Bar protein in the basal undifferentiated cells posterior to the furrow are dynamically regulated by multiple mechanisms during retinal differentiation. First, Hh signaling from the posterior margin induces the initial Bar expression at the posterior region of the disc at the early third instar stage. Second, during furrow migration, Ato-mediated EGFR activation in the furrow is required for the induction of Bar expression right posterior to the furrow. Finally, Bar expression can be positively autoregulated, which may be necessary for maintaining an even level of Bar expression from the posterior margin to the region right behind the furrow. Thus, the induction and maintenance of Bar expression in the basal undifferentiated cells are tightly linked to the mechanism of furrow initiation and progression.
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Materials and methods |
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Misexpression and generation of loss-of-function (LOF) mosaic clones
Progeny flies from the cross between UAS-BarH1M13 (or
UAS-BarH2F11) females and
BarP058-lacZ; decapentaplegic
(dpp)-GAL4/+ males were cultured at 25°C until
dissection at the third instar larval stage. LOF clones were generated by the
FLP/FRT system (Xu and Rubin,
1993). First instar larvae of the following genotypes were
heat-shocked for 1 hour at 37°C and then incubated at 25°C until
dissection: (1) lz LOF clones were obtained in lzr15
FRT18A/Ubi-GFP FRT18A;hs-FLP3; (2) ato LOF clones were
obtained in ey-FLP; ato1 FRT82B/Ubi-GFP FRT82B;
(3) egfr LOF clones were obtained in yw, hs-FLP;
egfrCO, GMR-P35 FRT42D/arm-lacZ, M(2)561 FRT42D; and (4)
smo LOF clones were obtained in hs-FLP; smo3
FRT40A/arm-lacZ FRT40A.
Immunocytochemistry
Third instar eye imaginal discs were dissected in phosphate-buffered saline
(PBS) on ice, fixed in 2% paraformaldehyde-lysine-periodate fixative and
stained as described (Carroll and Whyte,
1989). The following primary antibodies were used in this study:
mouse anti-ß-gal (1:250; Promega), mouse anti-Elav [1:10; Developmental
Studies Hybridoma Bank (DSHB)], mouse anti-GFP (1:200; Upstate biotechnology),
mouse anti-Lz (1:500; DSHB), mouse anti-dpERK (1:250; Sigma), rabbit anti-Ato
(1:5000) (Jarman et al.,
1995
), rabbit anti-BarH1 (1:100)
(Higashijima et al., 1992
),
rabbit anti-GFP (1:2000; Molecular Probes), guinea pig anti-Dlg (1:1000;
provided by P. Bryant) and guinea pig anti-Ato (1:1000)
(Hassan et al., 2000
).
Secondary antibodies were anti-mouse-CY3, anti-mouse-fluorescein isothocyanate
(FITC), anti-rabbit-CY3, anti-rabbit-FITC and antiguinea pig-CY5 (Jackson
Immunochemicals). Fluorescent images were scanned using Zeiss LSM
laser-scanning confocal microscope and processed with Adobe Photoshop.
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Results |
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Lz is expressed in R1, 6 and 7 photoreceptor cells and is required for
normal level of Bar expression in R1/6 cells
(Daga et al., 1996;
Flores et al., 1998
). In the
basal undifferentiated cells, Lz is co-expressed with Bar in a majority of
Bar-expressing cells (Fig. 1C,
white arrow), except in a group of cells just posterior to the furrow
(Fig. 1C, yellow arrow). To
test whether Lz is also required for Bar expression in the basal
undifferentiated cells, we examined Bar expression in homozygous
lzr15 mutants (data not shown) and loss-of-function (LOF)
clones of lzr15, a null allele of lz
(Daga et al., 1996
)
(Fig. 1D-I). We found that the
expression level of Bar was strongly decreased but not completely eliminated
in R1/6 photoreceptor cells within lzr15 mutant clones
(Fig. 1D-F), consistent with
the previous report (Daga et al.,
1996
). However, Bar expression in the basal undifferentiated cells
was little changed compared with its expression level in adjacent wild-type
cells (Fig. 1G-I). These
results suggest that Lz is necessary to activate Bar expression in R1/6 cells,
but not in the basal undifferentiated cells behind the furrow.
Next, we tested whether Gl, a zinc-finger protein expressed in all cells
posterior to the furrow (Moses and Rubin,
1991), is required for Bar expression in the basal
undifferentiated cells (Fig.
1K,L). Gl was not necessary for Bar expression in the basal
undifferentiated cells although it was essential for Bar expression in R1/6
photoreceptor cells (Fig. 1K,L)
(Higashijima et al., 1992
).
Taken together, these results suggest that Bar expression requires other
activators in the basal undifferentiated cells.
Bar expression in the basal undifferentiated cells depends on nonautonomous signals from the posterior margin
To identify the genes involved in activating Bar expression in the basal
undifferentiated cells, we examined where this activator(s) is required in the
developing eye disc. This factor(s) may be expressed in the Bar-expressing
cells for cell-autonomous activation of Bar expression in the basal
undifferentiated cells. Alternatively, it may be expressed in differentiating
photoreceptor cells and secreted to induce nonautonomous Bar expression in the
basal undifferentiated cells. To test whether Bar expression in the basal
undifferentiated cells depends on differentiating cells, we examined Bar
expression in ato1 mutant eye disc. Ato protein encoded by
ato1 is non-functional due to a mutation in the
DNA-binding domain and thus fails to induce neural differentiation
(Jarman et al., 1994;
Jarman et al., 1995
).
Morphogenetic furrow can be formed and progresses anteriorly to a certain
distance in the ato1 mutant eye disc, although retinal
differentiation fails to occur (Fig.
2A-C) (Jarman et al.,
1994; Jarman et al.,
1995
). Even in ato1 mutant eye disc, we
detected Bar expression posterior to the Ato stripe expression
(Fig. 2D-F; more than 20 discs
observed). This suggests that Bar expression depends on some activator(s)
produced from non-neuronal cells as no photoreceptors are generated in
ato1 mutant eye disc
(Jarman et al., 1994
;
Jarman et al., 1995
).
Interestingly, Bar expression level in ato1 mutant was
high near the posterior margin of eye disc but significantly decreased near
the furrow (Fig. 2F). This
suggests that Bar expression depends on a molecule secreted by non-neuronal
cells in the posterior margin, and its concentration becomes limited in the
region near the furrow as it progresses anteriorly from the posterior margin
(Fig. 2F).
|
To test whether Hh signaling from the posterior margin plays a role for
initial Bar expression in the basal undifferentiated cells, we generated LOF
clones of smoothened (smo), which is an essential component
for the transduction of Hh signaling
(Alcedo et al., 1996;
van den Heuvel and Ingham,
1996
; Strutt and Mlodzik,
1997
). We examined Bar expression within smo LOF clones
generated adjacent to the posterior margin of the disc
(Fig. 3A-D; more than 20 clones
observed). Bar expression was strongly reduced or absent within the relatively
large smo LOF clone (Fig.
3C, white arrow), although its expression was partially rescued
near clone borders (Fig. 3C,
yellow arrow). Photoreceptor differentiation failed to occur within
smo LOF clones when the posterior margin of the disc was included in
the clone (data not shown). Taken together, this suggests that Hh from the
posterior margin is crucial for initial Bar expression in the basal
undifferentiated cells near the posterior margin and that the graded Bar
expression in ato1 mutant eye disc
(Fig. 2D-F) is probably due to
Hh secreted from the posterior margin of the disc.
|
Bar expression requires Ato-mediated EGFR signaling from the morphogenetic furrow
Unlike the graded Bar expression pattern in ato1 mutant
eye disc (Fig. 2D-F), Bar
expression in the basal undifferentiated cells in the wild-type eye disc is
relatively even from the posterior margin of the disc to posterior the furrow
(Fig. 4A,B). In order to
establish such even distribution of Bar level, Bar expression may require
additional activators derived from the furrow region in addition to the
posterior margin Hh signaling (Fig.
4C).
|
An interesting question is what is the Ato-mediated nonautonomous signal
for Bar expression near the furrow. During early retinal neurogenesis, Ato
induces nonautonomous signals through the activation of EGFR signaling within
the proneural clusters (Fig.
4G-I) (Chen and Chien,
1999; Lesokhin et al.,
1999
), which is essential for ommatidial spacing by repressing Ato
expression in cells between the proneural clusters
(Kumar et al., 1998
;
Spencer et al., 1998
;
Chen and Chien, 1999
;
Lesokhin et al., 1999
;
Wasserman et al., 2000
;
Baonza et al., 2001
;
Yang and Baker, 2001
;
Frankfort and Mardon, 2002
).
As EGFR activity is also known to be required for Bar expression in the leg
disc (Campbell, 2002
), we
tested whether EFGR signaling can mediate Ato effects on Bar expression in the
eye disc (Fig. 4J-L). Indeed,
loss of egfr function failed to induce Bar expression immediately
posterior to the furrow within the clone
(Fig. 4K, white arrow; six
clones scored). Interestingly, Bar expression was not affected in the
posterior part of the egfr LOF clone
(Fig. 4K, yellow arrow), as
similarly seen in the ato1 LOF clone
(Fig. 4F, yellow arrow). In
addition, when egfr activity was removed at the restrictive
temperature in egfrts mutant
(Kumar et al., 1998
), Bar
expression was downregulated in the eye and antenna discs (data not shown).
These data suggest that EGFR is required for induction of Bar expression right
posterior to the furrow, although Bar expression may be induced by other
activators in the posterior region of the egfr LOF clones. Consistent
with the role of EGFR in the activation of Bar expression, loss of
egfr caused ectopic Ato expression within egfr mutant clones
behind the furrow due to loss of Bar expression
(Fig. 4L, yellow line). Taken
together, these data suggest that Ato-mediated activation of EGFR signaling in
the furrow induces Bar expression in the basal undifferentiated cells right
posterior to the furrow.
Bar autoregulates its expression
Bar expression in the basal undifferentiated cells depends on the function
of Hh- and Ato-dependent EGFR signaling from posterior and anterior,
respectively. Next, we asked whether Bar expression in the basal
undifferentiated cells in the middle of the disc is maintained as the furrow
proceeds further anteriorly in late third instar stage. To address this
question, we used an eye-specific hh1 mutant allele that
causes precocious furrow stop during third instar larval stage
(Heberlein et al., 1993). In
hh1 mutant eye disc, Hh is normally produced in
photoreceptor cells and functions until mid-third instar stage but is lost
after mid-third instar stage of development, resulting in a furrow arrest
(Fig. 5A-C). As Ato expression
depends on Hh signaling (Borod and
Heberlein, 1998
; Dominguez,
1999
), Ato expression was absent or strongly downregulated in the
late third instar hh1 mutant eye disc
(Fig. 5A-C). In the late third
instar hh1 mutant eye disc, Bar expression was quite
normal posterior to the arrested furrow
(Fig. 5A-C). This suggests that
Bar expression is maintained in the absence of Hh and Ato once it is initiated
by these signals.
|
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Discussion |
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|
Hh signaling is required for Bar expression in the basal undifferentiated cells during initial eye development because Bar expression was strongly reduced or absent within smo LOF clones generated near the furrow or close to the posterior margin of the disc (Fig. 3). Prior to the photoreceptor differentiation, Hh expressed in the posterior margin of the disc is responsible for Bar expression at specific distances from the posterior region of the eye disc proper. A graded expression of Bar near the posterior region in ato1 mutant eye disc (Fig. 2D-F) might be the effects of Hh secreted by the posterior margin.
During furrow progression, Hh signaling is required for Ato expression in
the furrow (Borod and Heberlein,
1998; Dominguez,
1999
), and Ato-mediated EGFR signaling is required for Bar
activation (Fig. 4D-L).
Therefore, it is possible that the loss of Bar expression near the furrow in
smo LOF clones might be caused by indirect effects of reduced Ato
expression rather than by direct effects of Hh signaling on Bar expression. Hh
may partially contribute to Bar expression by activating normal levels of Ato
expression in the furrow. Thus, the Hh-Ato-EGFR cascade activates Bar
expression right posterior to the furrow. Alternatively, as Hh signaling may
also affect furrow progression (Heberlein
et al., 1993
; Ma et al.,
1993
; Dominguez and Hafen,
1997
; Strutt and Mlodzik,
1997
; Borod and Heberlein,
1998
; Greenwood and Struhl,
1999
; Curtiss and Mlodzik,
2000
), it is possible that the loss of Bar expression near the
furrow in smo LOF clones might be caused by indirect effects of slow
furrow migration rather than by direct effects of Hh signaling on Bar
expression.
Effects of Ato-mediated EGFR signaling in Bar expression
Our results suggest that Ato is required nonautonomously for the induction
of Bar expression right posterior to the migrating furrow
(Fig. 4D-F). Although Ato acts
as an activator for Bar expression, expression of these proteins always show a
juxtaposed complementary pattern along the furrow (data not shown). This
suggests that some mediator(s) is required for transducing Ato effects on Bar
expression. EGFR activated by Ato in the furrow is required for Bar
expression, suggesting that nonautonomous effects of Ato on Bar expression may
be partially mediated by EGFR (Fig.
4D-L). Furthermore, EGFR is required for Bar expression not only
in the eye disc but also in the antenna and leg discs in Drosophila
(data not shown) (Campbell,
2002), suggesting that EGFR signaling may be a common activator
for Bar expression in different tissues or even in higher organisms.
Notch (N) signaling is also known to contribute to neuronal differentiation
together with Hh and Dpp pathways (Baker
and Zitron, 1995; Li and
Baker, 2001
; Frankfort and
Mardon, 2002
). Thus, N signaling may play a role for Bar
expression in the basal undifferentiated cells during furrow progression. Bar
expression was strongly downregulated when N function was removed
with a temperature-sensitive mutation (Nts) or using the
Enhancer-of-split [E(spl)] mutant clones in the eye disc
(data not shown). This suggests that N signaling may be required for Bar
expression in the basal undifferentiated cells. However, it is equally
possible that loss of Bar expression in the E(spl) LOF clones or in
the Nts eye disc may be an indirect secondary effect of
the lack of the basal undifferentiated cells because nearly all cells in the
basal region of the eye disc differentiate into photoreceptor cells without
N function. Further analysis of Bar regulation at the molecular level
will be helpful to identify direct regulators of Bar expression in the
undifferentiated cells of the eye disc.
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ACKNOWLEDGMENTS |
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