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First published online 24 January 2007
doi: 10.1242/dev.02788
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Research Report |
Department of Molecular, Cell and Developmental Biology, Department of Biological Chemistry, Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA.
* Author for correspondence (e-mail: banerjee{at}mbi.ucla.edu)
Accepted 29 November 2006
SUMMARY
In the developing eye of Drosophila, the EGFR and Notch pathways integrate in a sequential, followed by a combinatorial, manner in the specification of cone-cell fate. Here, we demonstrate that the specification of primary pigment cells requires the reiterative use of the sequential integration between the EGFR and Notch pathways to regulate the spatiotemporal expression of Delta in pupal cone cells. The Notch signal from the cone cells then functions in the direct specification of primary pigment-cell fate. EGFR requirement in this process occurs indirectly through the regulation of Delta expression. Combined with previous work, these data show that unique combinations of only two pathways - Notch and EGFR - can specify at least five different cell types within the Drosophila eye.
Key words: Drosophila, Notch, Pigment cells, EGFR, Lz, Combinatorial signaling
INTRODUCTION
A majority of cell-fate-specification events during metazoan development depend upon short-range signaling between adjacent cells. Given the extensive array of cell types in most multicellular organisms and the rather limited number of conserved signaling pathways, one must postulate that these pathways will function reiteratively during development. However, it is unclear how temporal specificity is generated such that, in a given tissue, the same signaling components used at different times mediate unique fate-specification events. In this study, we use the Drosophila eye as a model to demonstrate that two multifunctional signaling pathways can function reiteratively to generate several different cell fates from a set of pluripotent precursors.
The Drosophila eye has long been used to study cell fate
specification mediated by short-range intercellular signals between adjacent
cells (Freeman, 1997
;
Ready et al., 1976). Studies
from several laboratories have shown that EGFR and Notch function in multiple
events in the developing Drosophila eye (reviewed in
Baker, 2001;
Freeman, 2002;
Voas and Rebay, 2004).
Activation of EGFR by its ligand initiates the canonical Ras-Raf-MAPK pathway,
culminating in the phosphorylation of the ETS-domain protein Pointed (Pnt),
which binds to upstream enhancer elements and promotes transcriptional
activation (reviewed in Shilo,
2005). Likewise, activation of the Notch receptor in the eye by
its ligand Delta causes a cascade of proteolytic events resulting in the
generation of a cleaved intracellular domain, Notchintra, which
migrates to the nucleus, binds to Su(H) and activates the transcription of
target genes (reviewed in
Artavanis-Tsakonas et al.,
1999). Both EGFR and Notch pathways are regulated at the level of
ligand expression, as the receptors and the components downstream of them are
ubiquitously expressed.
The developing Drosophila eye disc exhibits two phases of
patterning as cells exit from the morphogenetic furrow, which is a dynamic
zone for cell-fate-specification events. In the first phase, groups of five
cells (R8, R2/R5, R3/R4) attain photoreceptor fate and constitute the
`precluster'. The rest of the cells undergo a terminal round of cell division
and form a pool of multipotent undifferentiated cells that contribute to the
formation of both neuronal (R1, R6 and R7) as well as non-neuronal (cone and
pigment) cell types. The differentiation of all of these cell types is
dependent on the function of EGFR, Notch and the Runt-domaincontaining protein
Lozenge (Lz) (reviewed in Nagaraj et al.,
2001). Depending upon the context, the EGFR and Notch pathways
function either in a synergistic or antagonistic fashion in the specification
of unique cell fates (Flores et al.,
2000; Yang and Baker,
2006). In photoreceptor cells (R cells), EGFR activation promotes
the transcription of Delta by a proteasome-mediated mechanism
involving the nuclear proteins Sno and Ebi
(Tsuda et al., 2002). This is
a derepression mechanism in which EGFR/Sno/Ebi promote the nuclear export of
SMRTER, disrupting the Su(H)-SMRTER repressor complex that keeps
Delta repressed. Thus, EGFR activation provides a localized source of
Notch signal that leads to a sequential integration of the Notch and EGFR
pathways during development (Fig.
1A). Delta that is expressed in the R cells then signals the
adjacent undifferentiated cells and promotes their differentiation into cone
cells. In addition to Notch, the specification of cone-cell fate also requires
EGFR activation and the transcription factor Lz. The earliest marker for this
cell fate is the expression of the Drosophila Pax2 (D-Pax2) protein
(Fu and Noll, 1997), the
expression of which is controlled in cone cells by the direct binding of Pnt,
Su(H) and Lz (Flores et al.,
2000). This highlights the importance of direct integration of
signaling pathways in a combinatorial fashion to activate key cell-fate
regulators.
Genetic studies have suggested that later in the pupal eye discs,
specification of the primary pigment-cell fate involves Notch and EGFR
(Cagan and Ready, 1989a;
Cagan and Ready, 1989b;
Freeman, 1996;
Miller and Cagan, 1998), but
their precise role has not been defined. In this paper we show that EGFR
activation in the pupal cone cells causes the transcriptional upregulation of
Delta. The activation of the Notch signal in the adjacent undifferentiated
cells in combination with Lz expression promotes their specification into
primary pigment cells. Thus, the entire logic of sequential integration of
EGFR and Notch pathways is used reiteratively to regulate the spatiotemporal
expression of Delta in R cells and then again later in cone cells. This Notch
signal then integrates with the cell-type-specific transcription factor Lz in
a cell autonomous manner, independently of the EGFR pathway, in the
specification of primary pigment-cell fate.
MATERIALS AND METHODS
Drosophila stocks
UAS-EGFRDN, UAS-NDN,
UAS-ebiDN and UAS-Delta (UAS-Dl) were
obtained from the Bloomington stock center. UASEGFRact on
the third chromosome was obtained from T. Suchpbach
(Queenan et al., 1997).
EGFRTo1 and EGFRts1 were obtained from
K. Moses (Kumar et al., 1998).
FRT42D EGFRts1 was obtained from G. Campbell
(Wang et al., 2000).
spa-Gal4 was obtained from M. Noll
(Kronhamn et al., 2002).
54C-Gal4 driver line was obtained from R. Cagan.
UAS-Su(H)DN was generated using Xenopus Su(H) DNA
binding mutant cDNA [obtained from C. Kintner
(Wettstein et al., 1997)],
cloned in a pUAST vector and transgenic flies generated using standard
procedures.
Heat-shock protocols
For the temperature-shift experiments involving Nts and
EGFRts, lzts114 white pupae were
collected and heat pulsed for 10 hours during the mid-pupal stages (10-20
hours after pupal formation). Pupal eye disc were dissected and stained with
the appropriate antibodies.
For heat-shock experiments involving the expression of EGFRDN
and NDN, white pupae were collected and heat pulsed at 30°C for
12 hours during the mid-pupal stages (10-25 hours after pupal formation).
Pupal eye disc were dissected and stained using anti-Bar antibody
(Hayashi et al., 1998).
EGFRts clones
EGFRts1 clones were generated using the
ey-flp/FRT system (Newsome et
al., 2000). The cross was maintained at 18°C. White pupae from
the cross were collected and subjected to a non-permissive temperature
(29°C) for 10 hours during the mid-pupal stages. Pupal eye discs were
dissected following heat shock and stained with anti-Delta or anti-Cut
antibody.
Immunohistochemistry
Larval or pupal eye discs were dissected in PBS and fixed in 4%
formaldehyde in PBS for 40 minutes. The fixed tissue was permeabilized in PBST
(0.4% Triton) and incubated in primary antibody [anti-Delta, 1/100; anti-Bar
1/50; anti-Cut, 1/20; anti-Dlg, 1/20; and anti-ß-Gal, 1/50 (mouse;
Promega) and 1/200 (rabbit; Capel)] overnight, washed in PBST three times and
incubated in an appropriate secondary florescent-labeled antibody. Images were
captured using a BioRad Confocal microscope.
RESULTS AND DISCUSSION
The events leading to the activation of Delta in the photoreceptor cells of
the third instar eye disc are summarized in
Fig. 1A (see also
Flores et al., 2000;
Tsuda et al., 2002). Unlike R
cells, cone cells do not express Delta at this stage of development
(Parks et al., 1995). However,
we found that these same cone cells express Delta at the pupal stage
(Fig. 1B,C). In addition,
correlated with this Delta expression, we observed the upregulation of
phosphorylated MAPK in these cells (Fig.
1D-F). This is very similar to the earlier events seen in R cells
during larval development, in which the activation of MAPK causes the
expression of Delta (Tsuda et al.,
2002). Also, as in the larval R cells, the pupal upregulation of
Delta in cone cells is transcriptional. The Delta-lacZ reporter
construct, off in the larval cone cell
(Fig. 1G-I), is detected in the
corresponding pupal cone cells (Fig.
1J-L). To determine whether EGFR is required for the activation of
Delta in the pupal cone cells, we used the temperature-sensitive allele
EGFRts1 (Kumar et al.,
1998). We generated marked clones of this allele in the eye disc
using ey-flp at permissive conditions and later, in the mid-pupal
stages, shifted the larvae to a non-permissive temperature. Cells mutant for
EGFR, but not their adjacent wild-type cells, showed a loss of Delta
expression (Fig. 2A-C).
However, both mutant and wild-type tissues showed normal cone-cell
development, as judged by Cut (a cone-cell marker) expression
(Fig. 2D-F). As supporting
evidence, ectopic expression of a dominant-negative version of EGFR
(EGFRDN) in cone cells using spa-Gal4 after the
cells have already undergone initial fate specification also causes a complete
loss of Delta expression without compromising the expression of the
cone-cell-fate-specification marker (Fig.
2G-J).
Gain-of-function studies further support the role of EGFR signaling in the
regulation of Delta expression in cone cells. Although weak EGFR activation is
required for cone-cell fate (Flores et al.,
2000), activated MAPK is not detectable in cone-cell precursors of
the third instar larval eye disc (Fig.
2K). When spa-Gal4 is used to express an activated
version of EGFR in larval cone cells, detectable levels of MAPK activation in
these cells were found (Fig.
2L) and the consequent ectopic activation of Delta in the larval
cone cells occurred (Fig.
2M,N). Taken together, these gain- and loss-of-function studies
show that, during pupal stages, EGFR is required for the activation of Delta.
However, this Delta expression is not essential for the maintenance of
cone-cell fate.
In larval R cells, the activation of Delta transcription in response to
EGFR signaling is mediated by two novel nuclear proteins, Ebi and Sno
(Tsuda et al., 2002). To
determine the role of these genes in wild-type pupal-cone-cell Delta
expression (Fig. 3A-C), we
selectively blocked sno and ebi function in the pupal eye
disc. A heteroallellic combination of the temperature-sensitive allele
snoE1 and the null allele sno93i
exposed to a non-permissive temperature for 12 hours caused a significant
reduction in Delta expression (Fig.
3D-F). Similarly, a dominant-negative version of ebi
(Dong et al., 1999) also caused
the loss of Delta expression (Fig.
3G-I). Importantly, pupal eye discs of neither spa-Gal4,
UAS-ebiDN nor
snoE1/sno93i showed any
perturbation in cone-cell fate, as judged by the expression of Cut
(Fig. 3F,I). Thus, as in the
case of larval R cells (Tsuda et al.,
2002), the loss of ebi and sno in the pupal cone
cells causes the loss of Delta expression without causing a change in
cone-cell fate.
To test whether the expression of Delta in pupal cone cells is required for
the specification of primary pigment cells, we incubated
Nts pupae at a non-permissive temperature for 10 hours
during pupal development and monitored pigment-cell differentiation using
BarH1 (also known as Bar) expression (Fu
and Noll, 1997; Hayashi et
al., 1998) as a marker (Fig.
4A). Loss of Notch signaling during the mid-pupal stages caused a
loss of Bar, further demonstrating the requirement of Notch signaling in the
specification of primary pigment-cell fate
(Fig. 4B). Similarly, when the
54CGal4 driver line, which is activated in pigment cells, was used to
drive the expression of a dominant-negative version of Notch
(Go et al., 1998), pupal eye
discs lost primary pigment-cell differentiation, again suggesting an
autonomous role for Notch in pigment-cell precursors
(Fig. 4C). In neither the
Nts nor the 54C-Gal4, UAS-NDN genetic
background, no perturbation was observed in cone-cell fate specification
(Fig. 4D-F). We conclude that
Delta activation mediated by EGFR-Sno-Ebi in pupal cone cells is essential for
neighboring pigment-cell fate specification.
Delta-protein expression in pupal cone cells is initiated at 12 hours and
is downregulated by 24 hours of pupal development
(Parks et al., 1995). To
determine the functional significance of this downregulation, we used the
genetic combination of spa-Gal4/UAS-Delta, in which Delta is
expressed in the same cells as in wild type, but is not temporally
downregulated (Fig. 4G).
Whereas, in wild type, a single hexagonal array of pigment cells surrounded
the ommatidium (Fig. 4H), in
the pupal eye disc of spa-Gal4, UAS-Delta flies, multiple rows of
pigment cells were observed surrounding each cluster
(Fig. 4I). Furthermore, in wild
type, only two primary pigment cells were positive for Bar expression in each
cluster (Fig. 4A), whereas, in
spa-Gal4, UAS-Delta pupal eye discs, ectopic expression of Bar was
evident in the interommatidial cells (Fig.
4J). Therefore, the temporal regulation of Notch signaling and its
activation, as well as its precise downregulation, are essential for the
proper specification of primary pigment-cell fate.
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The Runt-domain protein Lz functions in the fate specification of all cells
in the developing eye disc arising from the second wave of morphogenesis
(Daga et al., 1996). At a
permissive temperature (25°C), lzTS114
(Gupta and Rodrigues, 1995)
pupal eye discs showed normal differentiation of primary pigment cells
(Fig. 5D).
lzTS114 is a sensitized background in which the Lz protein
is functional at a threshold level. When combined with a single-copy loss of
Delta, a dosage sensitive interaction caused the loss of primary
pigment cells (Fig. 5E). By
contrast, under identical conditions, a single-copy loss of EGFR function had
no effect on the proper specification of primary pigment-cell fate
(Fig. 5F). This once again
supports the notion that the specification of primary pigment cells directly
requires Lz and Notch, whereas EGFR is required only indirectly to activate
Delta expression in cone cells.
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). Here, we show that EGFR activation in the pupal eye disc is
required for the transcriptional activation of Delta in cone cells, but that
the loss of EGFR function at the time when primary pigment cells are specified
does not perturb their differentiation. We conclude that the ectopic primary
pigment cells seen in an activated-EGFR background result from the ectopic
activation of Delta, which then signals adjacent cells and promotes their
differentiation into primary pigment cells. Indeed, we show here that
excessive Delta activity results in the over specification of primary pigment
cells. Our results are also consistent with the previous observation that the
EGFR target gene Argos is not expressed in primary pigment cells in pupal eye
discs (Wildonger et al.,
2005). Additionally, Frankfort and Mardon have shown that the loss
of EGFR function in pupal eye discs does not perturb the normal patterning of
interommatidial bristle development, which develop even later than the primary
pigment cells (Frankfort and Mardon,
2004).
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). However, studies from several laboratories have suggested
that the Sevenless pathway seems to be an exception, in that
cell-fate-specification events usually require reiterative combinations of a
very small number of non-specific signals
(Voas and Rebay, 2004).
Cone-cell fate is determined by the sequential integration of the EGFR and
Notch pathways in R cells followed by the parallel integration of the EGFR and
Notch pathways in cone-cell precursors
(Flores et al., 2000;
Tsuda et al., 2002;
Xu et al., 2000). Here, we
show that the most important function of EGFR in the specification of primary
pigment cells is to promote the transcriptional activation of Delta in cone
cells through the EGFR-Ebi-Sno-dependent pathway. The sequential integration
of the EGFR and Notch pathways, first used in the larval stage for Delta
activation in R cells, is then reused a second time in cone cells to regulate
the spatiotemporal expression of Delta, converting the cone cells at this late
developmental stage to Notch-signaling cells. Delta present in the cone cell
then signals the adjacent undifferentiated cells for the specification of
primary pigment cells. For this process, the Notch pathway functions directly
with Lz but indirectly with EGFR. Through extensive studies of this system
(Cagan and Ready, 1989a;
Cagan and Ready, 1989b;
Flores et al., 2000;
Freeman, 1996;
Tomlinson and Struhl, 2001;
Xu et al., 2000) it now seems
conclusive that different spatial and temporal combinations of Notch and EGFR
applied at different levels can generate all the signaling combinations needed
to specify the neuronal (R1, R6, R7) and nonneuronal (cone, pigment) cells in
the second wave of morphogenesis in the developing eye disc
(Fig. 5H).
The EGFR and Notch pathways are sequentially integrated, in a manner
similar to that described here, in multiple locations during
Drosophila development. In the development of wing veins, EGFR that
is activated in the pro-vein cells causes the expression of Delta, which then
promotes the specification of inter-vein cells
(Shilo, 2005). Similarly,
these two pathways are sequentially integrated in the patterning of embryonic
and larval PNS, and during muscle development
(Artero et al., 2003;
Modolell, 1997). Indeed, there
are striking similarities between the manner in which the EGFR and Notch
pathways are integrated in the developmental program in the C.
elegans vulva and the Drosophila eye
(Sundaram, 2005). During
vulval fate specification in the C. elegans hermaphrodite gonad,
anchor cells are a source of EGFR signal (Lin3), which induces the
specification of the nearest (P6) cell to the primary cell fate from within a
group of six equipotent vulval precursor cells (VPC)
(Sternberg, 2005). This high
level of EGFR activation induces the transcriptional activation of Notch
ligands in the primary cells in what can be considered sequential integration
of the two pathways (Chen and Greenwald,
2004) - the Notch signal from the primary cell both inhibits EGFR
activity in the VPCS on either side of P6.p and also promotes the secondary
cell fate (Yoo et al., 2004).
Thus, the reiterative integration of these two signals, in series and in
parallel, can be used successfully to specify multiple cell fates in different
animal species. Given that the RTK and Notch pathways function together in
many vertebrate developmental systems, it is likely that similar networks will
be used to generate diverse cell fates using only a small repertoire of
signaling pathways.
ACKNOWLEDGMENTS
We thank G. Campbell, R. Cagan, K. Moses, M. Noll and T. Schupbach for fly stocks. We are grateful to T. Kojima for providing the anti-Bar antibody. Monoclonal anti-Delta, anti-Cut and anti-Dlg antibodies, developed by S. Artavanis Tsakonas, G. Rubin and C. Goodman, respectively, were obtained from the Developmental Studies Hybridoma Bank under the auspices of the NICHD and maintained by the University of Iowa, Department of Biological Sciences, Iowa City, IA 52242. This work was supported by NIH grant EY08152 to U.B.
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