1 Department of Molecular and Human Genetics, Baylor College of Medicine,
Houston, TX 77030, USA
2 Department of Pathology, Baylor College of Medicine, Houston, TX 77030,
USA
3 Department of Ophthalmology, Baylor College of Medicine, Houston, TX 77030,
USA
4 Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030,
USA
5 Program in Developmental Biology, Baylor College of Medicine, Houston, TX
77030, USA
* Author for correspondence (e-mail: gmardon{at}bcm.tmc.edu)
Accepted 24 October 2003
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SUMMARY |
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Key words: Senseless, Egfr, Pointed, Spitz, Drosophila melanogaster, R8
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Introduction |
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R8 development requires the actions of the proneural gene atonal
(ato) and its downstream effector, senseless
(sens), which encodes a conserved C2H2 zinc finger transcription
factor (Frankfort et al., 2001;
Jarman et al., 1994
;
Nolo et al., 2000
). Several
specific substages of R8 development have been identified (reviewed by
Frankfort and Mardon, 2002
). In
particular, there is a distinction between R8 selection, the choosing of an R8
precursor from a group of developmentally equivalent cells, and R8
differentiation, a later process by which R8 fate is `locked' and the
expression of neural markers is initiated. sens is required only in
R8, and mutations in sens result in a total failure of R8
differentiation despite normal selection of R8 precursor cells (called
presumptive R8s, or pre-R8s) (Frankfort et
al., 2001
; Nolo et al.,
2000
). Furthermore, in sens mutants, the pre-R8 cell
instead consistently differentiates as a founder photoreceptor of the R2/R5
subtype (Fig. 1B)
(Frankfort et al., 2001
;
Nolo et al., 2000
). R2/R5 is
normally the first subtype of paired non-R8 photoreceptors to be recruited by
Egfr activation via Spi secretion from R8
(Fig. 1A) (Tomlinson and Ready, 1987
).
Like wild-type R2/R5 cells, the R2/R5 cells that develop from the pre-R8 in
sens mutants express Ro, which is required for R2/R5 differentiation
(Frankfort and Mardon, 2002
;
Kimmel et al., 1990
;
Tomlinson et al., 1988
).
R8 differentiation is restored when ro function is removed in
sens mutant tissue, suggesting that Sens-mediated repression of
ro is a critical event during R8 differentiation. However, complete
loss of ro function does not rescue R8 differentiation in all
sens mutant ommatidia. Therefore, it is probable that Sens also has a
function in R8 which is distinct from its role as a repressor of ro
(Frankfort et al., 2001). Since
the pre-R8 cell in sens mutants consistently differentiates as a cell
type that is normally Egfr dependent (R2/R5) and Egfr pathway activation
appears incompatible with R8 differentiation, it is possible that this
additional function of Sens may involve repression of Egfr signaling in R8
(Fig. 1C).
We show that Sens prevents transduction of Egfr signaling to the nucleus of R8, despite both Egf receptor activation and ERK phosphorylation. This is accomplished via a novel regulatory mechanism Sens causes the transcriptional repression of the P1 isoform of pointed. This ensures that the ommatidial signaling center is protected from the effects of autocrine stimulation by secreted Spi, and that R8 differentiation and normal ommatidial organization are preserved. Finally, analogous relationships that exist between Sens and Egfr pathway orthologs in T-lymphocytes may establish R8 development as a novel system with which to study lymphomagenesis, apoptosis and cancer.
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Materials and methods |
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The sca-GAL4 line was a gift from Yash Hiromi. This line is expressed at high levels in R8, beginning with the first column of single R8 cells and at lower levels in both other cells in the morphogenetic furrow and some non-R8 cells posteriorly (our unpublished observations).
Immunohistochemistry and visualization of adult eyes
All antibodies were used and confocal microscopy performed as previously
described (Frankfort et al.,
2001). Adult eyes were fixed, embedded and sectioned as previously
described (Frankfort et al.,
2001
). Whole adult eyes were examined using a Leica MZ16
stereomicroscope and processed with Image-Pro Plus image analysis
software.
Generation of UAS-rough
proc4-2 (Tomlinson et al.,
1988), was digested with EcoRI to yield a 1.2 kb
ro cDNA lacking the coding sequence for the first four amino acids.
This fragment was subcloned into pBluescript containing an EcoRI
site, which was modified with the following adapters:
5'-AATTGCCTCAAACGAAATGCAG and 5'-AATTCTGCATTTCGTTTGAGGC. This
created a modified ro cDNA that encodes a protein N terminus of
MQNSSK instead of the wild-type MQRHK. Several protein and biochemistry
prediction programs were used to assess the modified ro cDNA and no
changes in behavior compared to wild-type were predicted. The ro cDNA
was then excised from pBluescript with an XhoI/XbaI
digestion and directionally cloned into pUAST. Vector DNA was injected into
Drosophila embryos according to standard protocols. Ro protein was
detected in wing and leg imaginal discs by antibody staining when
UAS-ro was misexpressed with dpp-GAL4, and transgenic
UAS-ro animals were sufficient to rescue the
roX63 mutant phenotype when misexpressed with
hsGAL4, suggesting that the encoded Ro protein is functional in vivo
(Kimmel et al., 1990
).
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Results |
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We tested this hypothesis by simultaneously removing sens function
and blocking Egfr activation in the developing Drosophila eye
(Fig. 2A-C). We blocked Egfr
activation by removing function of both rhomboid-1 (rho-1)
and rhomboid-3 (rho-3; FlyBase: roughoid, ru). Loss
of both rho-1 and rho-3 function prevents processing of
secreted Egfr ligands, including Spi, and results in the loss of all ERK (MAP
kinase) activation (Urban et al.,
2002; Wasserman et al.,
2000
). Furthermore, loss of rho-1 and rho-3
phenocopies Egfr loss-of-function in that only R8 cells differentiate
(Fig. 2A) (Wasserman et al., 2000
). Loss
of sens function results in pre-R8 differentiation as a founder R2/R5
cell which is sufficient to recruit a reduced number of photoreceptors
(Fig. 2B). However, the absence
of rho-1, rho-3 and sens together causes total photoreceptor
loss, except for a few photoreceptors near the clonal boundary that are
rescued non-autonomously by neighboring wild-type cells that produce and
process Spi appropriately (Fig.
2C) (Frankfort et al.,
2001
). A similar phenotype is detected in tissue mutant for both
spi and sens (Fig.
2D). This loss of photoreceptors seen in rho-1 rho-3 sens
and spi sens mutants is not due to cell death because apoptosis was
prevented in these experiments by expression of GMR-p35 (see
Materials and methods) (Hay et al.,
1994
). Furthermore, pre-R8 selection still occurs in both
rho-1 rho-3 and rho-1 rho-3 sens mutant tissue, suggesting
that a potential founding photoreceptor is present
(Fig. 2E,F). Therefore, our
interpretation of these results is that, in the absence of sens
function, pre-R8 differentiation as a founder R2/R5 photoreceptor requires
activation of the Egfr signaling pathway via the Spi ligand. In other words,
in sens mutants, the pre-R8 switches from a Spi/Egfr-independent R8
differentiation pathway to a Spi/Egfr-dependent R2/R5 differentiation
pathway.
Sens is a negative regulator of the Egfr pathway
When rho-1 and rho-3 function are removed in sens
ro double mutants, R8 differentiation does not occur
(Fig. 2G). This suggests that
the requirement in the pre-R8 cell for Egfr activation remains even when
ro function is removed, and that the ro-independent function
of sens may involve a relationship with the Egfr pathway.
Specifically, as the pre-R8 normally does not require Egfr activation but
becomes completely dependent on Egfr activation when sens function is
removed, we hypothesized that sens normally acts as a repressor not
only of ro, but also of Egfr pathway activation in R8. This potential
function of sens as a repressor of Egfr signaling is supported by
genetic interactions between sens and the gain-of-function
EgfrElp mutation. EgfrElp homozygotes
have a greatly reduced number of ommatidia with large gaps of pigmented tissue
between them (Fig. 3A)
(Baker and Rubin, 1989). In
contrast, sens mutant tissue is disrupted in appearance but does not
contain undifferentiated gaps between ommatidia
(Fig. 3B)
(Frankfort et al., 2001
).
However, when clones of sens mutant tissue are induced in a
background that is heterozygous for the EgfrElp mutation,
gaps of undifferentiated tissue appear between ommatidia, a phenotype very
similar to that of EgfrElp homozygotes
(Fig. 3C). Thus, loss of
sens function strongly enhances the EgfrElp
heterozygous phenotype such that it closely approximates that of
EgfrElp homozygotes. If this enhancement occurs by
derepression of Egfr signaling by the loss of sens function, then
misexpression of sens in an EgfrElp homozygote
might have the opposite effect and suppress the phenotype of ommatidial loss
and interommatidial gaps. Indeed, misexpression of UAS-sens with
ey-GAL4 has precisely these effects on EgfrElp
homozygotes (Fig. 3D).
Together, these gain- and loss-of-function experiments suggest that
sens functions as a powerful negative regulator of the Egfr pathway
during Drosophila eye development. Since the expression of Sens is
tightly restricted to R8 and the primary sens mutant phenotype occurs
in the pre-R8 cell, it is most likely that this repression occurs specifically
in the differentiating R8 photoreceptor. We therefore looked at expression of
an enhancer trap in pointed (pnt-lacZ), which encodes the
nuclear effector of the Egfr pathway. Consistent with our hypothesis,
pnt-lacZ, while expressed in many non-R8 photoreceptors as they
differentiate, is not expressed in Sens-expressing R8 cells
(Fig. 3E,F; Materials and
methods) (Scholz et al.,
1993
).
Sens blocks activation of Egfr signaling at the nuclear level
While the Egfr pathway is probably activated at a high level at the cell
membrane and in the cytoplasm of R8, expression of nuclear outputs of the
pathway is low (Fig. 3E,F, see
Introduction). Moreover, whereas loss-of-function mutations in all major Egfr
pathway members have no effect on R8 differentiation, high levels of
activation of Egfr signaling as a result of either ectopic expression or
EgfrElp mutations result in the development of very few R8
photoreceptors (Dominguez et al.,
1998; Kumar et al.,
1998
; Lesokhin et al.,
1999
; Yamada et al.,
2003
; Yang and Baker,
2001
). Thus, the reduction in Egfr activation from high
cytoplasmic levels to low nuclear levels in R8 may be of developmental
importance. Since Sens acts as a negative regulator of the Egfr pathway, we
hypothesized that Sens mediates this critical decrease in Egfr signaling from
membrane/cytoplasm to nucleus in R8.
To test this hypothesis, we ubiquitously expressed an activated form of
Egfr (Egfract) in small clones using flpout-GAL4.
We first looked at Egfract clones positioned posterior to
the morphogenetic furrow (MF). Neural differentiation occurs throughout such
clones (Fig. 4A). Since ectopic
Egfr activation is sufficient to induce photoreceptor differentiation prior to
passage of the MF, these clones probably represent a field of cells that had
already differentiated as neurons by the time the MF reached it
(Dominguez et al., 1998).
Consistent with the hypothesis that high levels of Egfr activation are not
compatible with R8 differentiation, these clones show a cell-autonomous lack
of Sens expression (Fig. 4A).
Anterior to the MF, activation of Egfr signaling causes precocious neural
development autonomously, and induces ectopic MFs non-autonomously. These
ectopic MFs express Ato, Sens and dpERK appropriately
(Fig. 4B,C)
(Dominguez et al., 1998
).
Furthermore, the ectopic neurons generated with this system express
pnt-lacZ at a high level, indicating that the nuclear target of Egfr
activation is being induced and the canonical Egfr signaling pathway is
probably the cause of neural differentiation
(Fig. 4D). However, when
sens is co-misexpressed along with Egfract,
pnt-lacZ expression is prevented and neural differentiation is severely
reduced in the cells that express sens, and ectopic MFs are not
established (Fig. 4E,F). In
contrast, dpERK expression still occurs when sens is co-misexpressed
with Egfract, indicating that the Egfr pathway is being
activated at the cell membrane and within the cytoplasm
(Fig. 4F). This suggests that
Sens cell-autonomously blocks transduction of the activated Egfr pathway to
the nucleus and is sufficient to prevent the effects of cell membrane
activation of the Egfr pathway. These results are also consistent with our
proposed role for Sens as a repressor of high levels of Egfr signaling in
R8.
Sens represses pointed-P1 in R8
If Sens acts to reduce Egfr signaling from the cytoplasm to the nucleus of
R8, we hypothesized that activation of Egfr signaling downstream of the point
at which Sens blocks the pathway could disrupt normal R8 differentiation,
whereas activation of the pathway upstream of this point would have little or
no effect. To test this hypothesis, we misexpressed members of the Egfr
pathway in R8 using sca-GAL4 (Materials and methods). When
Egfract or ras1val12 (an activated
form of Ras that functions in the cytoplasm upstream of ERK) is expressed in
R8 with this system there is no appreciable effect on Sens, Boss, or Ro
expression in third instar eye imaginal discs
(Fig. 5A-C, not shown). This
suggests that R8 differentiation proceeds normally when the Egfr pathway is
activated at the cell membrane or within the cytoplasm of R8 and is consistent
with our proposed role for Sens in R8. Since Sens acts as a repressor of
pnt transcription, we also misexpressed both isoforms of pnt
in R8. Interestingly, misexpression of the P2 isoform of pnt
(pnt-P2), or an activated form of pnt-P2, also has no effect
on R8 differentiation (not shown) (Halfon
et al., 2000). However, misexpression of pnt-P1 causes a
disruption in Sens expression such that Sens-expressing nuclei are displaced
apically in the imaginal disc (Fig.
5D,E). Since photoreceptor nuclei move basally during neuronal
differentiation, this implies that misexpression of pnt-P1 in R8 may
disrupt R8 differentiation. Consistent with this, many sca-GAL4
x UAS-pnt-P1 adult ommatidia do not contain small rhabdomeres,
suggesting an absence of R8 (Fig.
5F). Ommatidia also contain a variable number of photoreceptors
and these adult phenotypes are very similar to the sens
loss-of-function phenotype. These results imply that pnt-P1, but not
pnt-P2, may be a target of sens repression. Misexpression of
ro, an early target of Egfr signaling, has a more profound effect on
R8 development as both Sens and Boss expression are absent
(Fig. 5G, not shown). Adult
ommatidia lack small rhabdomeres but are otherwise of relatively normal
construction (Fig. 5H). These
results are consistent with the known function of ro as a critical
determinant of R2/R5 cell fate determination, as well as with our previous
model in which Sens acts as a repressor of ro. Together, these data
strongly suggest an important additional role for Sens as a novel nuclear
repressor of pnt-P1 (Fig.
6).
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Discussion |
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The mechanism by which Sens regulates the discrepancy between levels of
Egfr activation at the receptor/cytoplasmic and nuclear levels in R8 is
probably through repression of pnt transcription. This is supported
by the observation that pnt transcription is not induced by
misexpression of an activated form of Egfr when sens is
co-misexpressed (Fig. 4).
Furthermore, expression of the pnt-P1 isoform in R8 disrupts R8
differentiation (Fig. 5D-F). As
misexpression of pnt-P2 has no effect on R8 differentiation, this
suggests that Sens negatively regulates transcription of pnt-P1, but
not pnt-P2. This mode of regulation is consistent with established
models for transduction of the Egfr signal to the nucleus. Specifically, ERK
phosphorylates Pnt-P2, which is thought to be a transient positive regulator
of pnt-P1 transcription (Brunner
et al., 1994; O'Neill et al.,
1994
). In our model, transduction of Egfr activation occurs all
the way into the nucleus of R8, but Sens represses the pathway at the final
step positive regulation of pnt-P1 by Pnt-P2
(Fig. 6). When sens
function is removed, the block on pnt-P1 transcription is relieved,
and Pnt-P1 can exert its transcriptional effects on the nucleus, including
ro induction.
There is evidence that pnt-P1 transcription can be regulated by
Egfr signaling independently of pnt-P2 during Drosophila
embryogenesis (Gabay et al.,
1996). If this is the case during eye development, our model would
remain essentially the same Sens would still act as a negative
regulator of pnt-P1 in R8. However, this regulation would occur
independently of pnt-P2 rather than downstream of
pnt-P2.
Sens is also a potent negative regulator of ro and this
relationship appears to specifically affect the cell fate decision between R8
and R2/R5 differentiation (Fig.
5G,H) (Frankfort et al.,
2001). Several lines of evidence suggest that Sens-mediated
repression of ro is distinct from other effects of Sens in R8. First,
loss of ro function does not rescue R8 differentiation in all
ommatidia in sens mutants
(Frankfort et al., 2001
).
Second, even those R8 cells that do differentiate in sens ro double
mutants require Spi/Egfr pathway activation
(Fig. 2G). Third, misexpression
of ro in R8 causes a different phenotype than misexpression of
pnt-P1 in R8. Specifically, even though Egfr pathway activation is
necessary and sufficient for Ro expression, misexpression of pnt-P1
in R8 does not cause an obvious cell fate transformation from R8 to R2/R5,
while misexpression of ro in R8 does
(Fig. 5D-H)
(Dominguez et al., 1998
;
Hayashi and Saigo, 2001
).
Indeed, R8 markers are still expressed when pnt-P1 is misexpressed in
R8. However, aberrant nuclear movements and the absence of small rhabdomeres
at the level of R8 in adults suggest that misexpression of pnt-P1
does perturb R8 differentiation (Fig.
5D). Together, these results suggest that Sens repression of
pnt-P1 occurs independently of Sens function as a repressor of
ro, and that Sens-mediated repression of pnt-P1 is probably
required for normal R8 differentiation upstream or independently of cell fate
determination (Fig. 6).
Since Sens acts as a transcription factor and its mammalian homolog, Gfi-1,
binds directly to enhancer regions of Ets1 and Ets3, two
mammalian orthologs of pnt, is it possible that Sens repression of
pnt-P1 expression occurs directly
(Duan and Horwitz, 2003;
Nolo et al., 2000
;
Zweidler-Mckay et al., 1996
).
Gfi-1 also interacts with nuclear matrix proteins to repress transcription
(McGhee et al., 2003
). Thus,
it is possible that Sens represses transcription of Egfr nuclear effectors via
a similar mechanism. Future experiments are required to determine which of
these or other mechanisms are important during R8 differentiation. However, it
is likely that Sens does not act as a positive regulator of Edl/Mae, a
proposed cell-autonomous repressor of Egfr signaling, because edl/mae
function is not required for normal R8 differentiation
(Yamada et al., 2003
).
Finally, it is also unlikely that sens functions as an activator of
yan, which encodes a nuclear repressor of the Egfr pathway, because
yan loss-of-function mutations also do not impact R8 differentiation
(Lai and Rubin, 1992
).
Conservation of Sens/Egfr antagonism?
The positioning of Sens repression downstream of ERK activation may help
explain interactions observed between sens and Egfr pathway homologs
in T-lymphocytes. In Jurkat T-cells, activation induced cell death (AICD), a
process that is required to prevent non-specific activation of T-cells, is
dependent, in part, on ERK1/2 activation
(van den Brink et al., 1999).
Intriguingly, high levels of Gfi-1 have been shown to inhibit AICD despite
high levels of ERK1/2 activation (Karsunky
et al., 2002
). The antagonistic relationship between Sens and the
Egfr pathway in R8, in conjunction with the observation that Gfi-1 can bind to
the enhancer regions of Ets1 and Ets3, suggest that this
inhibition of AICD may occur via Gfi-1-mediated repression of ERK1/2 targets
(such as Ets/pnt) in T-cells (Duan
and Horwitz, 2003
). Thus, our results may establish R8 development
as a powerful and novel system with which to study mechanisms of
lymphomagenesis, apoptosis and cancer.
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ACKNOWLEDGMENTS |
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