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First published online 12 December 2007
doi: 10.1242/dev.008920
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1 Department of Chemical Engineering and Lewis-Sigler Institute for Integrative
Genomics, Princeton University, NJ 08544, USA.
2 Howard Hughes Medical Institute and Department of Molecular Biology, Princeton
University, NJ 08544, USA.
Author for correspondence (e-mail:
stas{at}princeton.edu)
Accepted 17 October 2007
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SUMMARY |
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 TOP SUMMARY INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key words: Cell signaling, Epithelial patterning, Feedforward control, Pattern formation, Drosophila
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INTRODUCTION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Biochemical and cellular mechanisms of signaling crosstalk
become progressively characterized, but the dynamics of pathway integration at
the tissue level remains poorly understood. Here we show how the
evolutionarily conserved EGFR and BMP pathways interact in a network that
controls epithelial patterning in Drosophila oogenesis, an
established genetic model for studying the connection between signaling and
developmental pattern formation (Deng and
Bownes, 1998; Dobens and
Raftery, 2000; Berg,
2005; Horne-Badovinac and
Bilder, 2005).
The three-dimensional shell of the Drosophila egg is derived from
the follicular epithelium in the developing egg chamber
(Fig. 1A),
(Spradling, 1993). Dorsal
eggshell structures, the respiratory dorsal appendages and the operculum, are
formed by the dorsoanterior follicle cells, which are patterned by Gurken
(Grk), an EGFR ligand secreted from the oocyte
(Schüpbach, 1987), and
Dpp, a Bmp2/4-like molecule produced by the stretch follicle cells
(Twombly et al., 1996;
Peri and Roth, 2000). Each
dorsal appendage is formed by two groups of dorsolateral follicle cells
(Dorman et al., 2004;
Berg, 2005). The roof of the
appendage is formed by cells expressing Broad (Br), a zinc-finger
transcription factor (Deng and Bownes,
1997; Tzolovsky et al.,
1999). The floor of the appendage is derived from the adjacent
domain of cells expressing rhomboid (rho), which encodes an
intracellular protease in the Drosophila EGFR pathway
(Ruohola-Baker et al., 1993;
Urban et al., 2001). Genetic
approaches have established that the wild-type expression patterns of both
br and rho depend on both EGFR and Dpp signaling
(Neuman-Silberberg and Schüpbach,
1994; Deng and Bownes,
1997; Peri et al.,
1999; Atkey et al.,
2006). However, the origin of the dynamics of br and
rho expression and their connection to eggshell patterning remained
unclear.
Eggshell morphology can be dramatically affected by variations in the
levels of Gurken and Dpp
(Neuman-Silberberg and Schüpbach,
1994; Twombly et al.,
1996; Dobens et al.,
2000). Given this degree of sensitivity, it is unclear how these
two inductive signals, which originate from two different tissues, coordinate
their actions in order to establish the elaborate gene expression patterns and
eggshell morphology. One mechanism for coordinating the actions of the EGFR
and Dpp pathways may involve signaling crosstalk. Indeed, recent studies have
shown that EGFR signaling influences the effects of Dpp by regulating the
expression of inhibitors of Dpp signaling and have demonstrated that this type
of pathway interaction is important for the formation of the Br expression
domain (Chen and Schüpbach,
2006; Shravage et al.,
2007).
Here we demonstrate that the patterning mechanism is considerably more complex. We found that, in addition to being a target of Dpp signaling, Br regulates the Dpp pathway in late stages of oogenesis by controlling the expression of the type I Dpp receptor thickveins (tkv). The Br-dependent changes in tkv expression lead to changes in the spatial pattern of Dpp signaling. As a result, the late phase of Dpp signaling in oogenesis has a clear dorsoventral polarity, in contrast to the early phase of Dpp signaling, which is uniform along the dorsoventral (DV) axis. We show that the early and late phases of Dpp signaling control different spatial domains of the br expression pattern. The early phase of Dpp signaling represses br in the anterior follicle cells, whereas the late phase of Dpp signaling limits the duration of br expression in the cells that form the roof of future dorsal appendages. We integrate these findings with the results of previous studies and propose a new model of eggshell patterning, in which the pattern of Br is established by the sequential action of feedforward and feedback loops.
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MATERIALS AND METHODS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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), X7;28.20 (which contains four copies of P[w+ grk+]
(Neuman-Silberberg and Schüpbach,
1993), EgfrQY1
(Schüpbach, 1987),
UAS-Dad (a gift from J. Duffy), CY2-Gal4
(Queenan et al., 1997;
Goentoro et al., 2006b),
D. pseudoobscura (a gift from V. Orgogozo and D. Stern). D.
virilis, and D. phalerata (a gift from J. Duffy). The FLP/FRT
mitotic recombination system (Xu and
Rubin, 1993; Duffy et al.,
1998) was used to generate clones of mutant follicle cells marked
by the absence of GFP. The following genotypes were used to analyze the
effects of the EGFR pathway: a null allele of Ras: e22c-Gal4
UAS-FLP; FRT82B
ras
C40b/FRT82B
ubi-GFP (Hou et al.,
1995; James et al.,
2002). Analyses of the effects of the BMP pathway used the
following alleles: Med1: e22c-Gal4 UAS-FLP;
FRT82B Med1/FRT82B
ubi-GFP, and a Mad12 allele:
FRT40A Mad12/FRT40A
ubiGFP;GR1-Gal4 UAS-FLP, and a tkv12 allele:
FRT40A tkv12/FRT40A
ubiGFP;GR1-Gal4 UAS-FLP. The Mad12,
Med1 and tkv12 mutant lines are a gift
from R. Padgett. Flies were grown on agar cornmeal medium; all crosses were
done at 23°C. In Br overexpression experiments, the UAS-Br-Z1 construct (a
gift from L. Riddiford) was driven by the Gal80-Gal4, CY2-Gal4
expression system (Suster et al.,
2004). Mosaic analysis of the effects of br-
cells were done with the brCJ89
FRT19A/FRT19A; e22c-Gal4 UAS-FLP
flies (Chen and Schüpbach,
2006).
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), but without the RNase digestion step. The
digoxigenin-labeled RNA probes were made from a cDNA clone of br-Z2
(kindly provided by W-M. Deng), tkv (kindly provided by M. O'Connor),
rho (Ruohola-Baker et al.,
1993), and the tkv clone from D. phalerata.
Immunofluorescence and microscopy
Dissection and fixation of ovaries was done as described elsewhere
(Pacquelet and Rorth, 2005).
Primary antibodies: mouse anti-Br core (25E9.D7; 1:100, DSHB), rabbit
anti-phosphorylated-Smad1/5/8 (1:3000, a generous gift from D. Vasiliauskas,
S. Morton, T. Jessell and E. Laufer), rabbit or mouse anti-GFP (1:2000,
Molecular Probes and Chemicon International, respectively), rabbit or mouse
Anti-HA monoclonal antibodies (1:2000, Chemicon) and Hoechst dye to stain the
nuclei (1:10,000). Secondary antibodies: Alexa Fluor and Oregon Green (1:2000,
Molecular Probes). Images were taken with a PerkinElmer RS3 Spinning Disk
Confocal microscope and the Nikon Eclipse E800 compound microscope. Images
were processed with ImageJ (Rasband, 1997-2006) and Photoshop (Adobe Systems,
San Jose, CA). ESEM images were taken as described elsewhere
(Yakoby et al., 2005).
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RESULTS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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; Pai et al.,
2000; Goentoro et al.,
2006a). The later pattern is mediated by Spitz, an EGFR ligand
secreted by the two L-shaped stripes of the follicle cells on either side of
the dorsal midline (Ruohola-Baker et al.,
1993; Sapir et al.,
1998; Wasserman and Freeman,
1998; Peri et al.,
1999).
In contrast to the dynamic pattern of EGFR activation, the pattern of Dpp
signaling is viewed as a static anteroposterior (AP) gradient that persists
through all stages of eggshell patterning
(Peri and Roth, 2000;
Berg, 2005;
Shravage et al., 2007). Before
stage 10 of oogenesis, such a pattern can be readily explained by a model in
which the anteriorly secreted Dpp acts through receptors that are uniformly
expressed throughout the follicular epithelium
(Peri and Roth, 2000;
Jekely and Rorth, 2003).
Later, however, the spatial pattern of the type I Dpp receptor tkv
acquires a clear DV polarity (Mantrova et
al., 1999). In stage 10B egg chambers, tkv is expressed
in a dorsoventral pattern with two lateral patches on both sides of the dorsal
midline (Fig. 1B-D).
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The AP-to-DV transition in the pattern of Dpp signaling is conserved across species
In contrast to recently published observations
(Shravage et al., 2007), our
results establish that the pattern of Dpp activation undergoes a clear
transition from the purely AP to the DV pattern in late stages of oogenesis.
Remarkably, we found that this transition is conserved in other fruit fly
species (Fig. 2A). The early
spatial patterns of P-Mad were uniform along the DV axis in egg chambers of
D. pseudoobscura, D. phalerata and D. virilis
(Fig. 2B,E,H). Later, however,
the P-Mad pattern in each of these species acquired a clear DV polarity, just
as it does in D. melanogaster
(Fig. 2C,F,I-K). For instance,
in D. phalerata, the anterior ring of P-Mad in mid-oogenesis
underwent a transition to a ventral band of P-Mad in older egg chambers
(Fig. 2I-K). Importantly, this
transition closely followed a similar transition in the expression of
tkv in this species (Fig.
2L-N).
Based on these observations, we made a number of predictions regarding the origin and significance of the Dpp signaling dynamics in mid- to late stages of oogenesis. First, based on the correlation between the spatial patterns of P-Mad and tkv, we predicted that the DV pattern of tkv controls the spatial pattern of Dpp signaling. Second, as the DV polarity in oogenesis is due to EGFR signaling, we predicted that the pattern of tkv depends on EGFR signaling. Finally, based on the evolutionarily conserved nature of AP-to-DV transition in the pattern of Dpp signaling, we predicted that this transition is functionally significant for eggshell patterning. We have used a combination of gain- and loss-of-function approaches to directly test each of the predictions in D. melanogaster.
The spatial pattern of tkv regulates the spatial pattern of Dpp signaling and is sensitive to EGFR signaling levels
To test whether tkv is essential for Dpp signaling in the
follicular epithelium, we generated GFP-marked clones of
tkv- cells and monitored the resulting change in the P-Mad
pattern. We found that P-Mad signal disappeared in clones of
tkv- cells, confirming the essential role of tkv
for Dpp signaling (Fig. 3A-C).
Thus, the midline repression of tkv at stage 10 of oogenesis
(Fig. 1C), can account for the
corresponding repression in the wild-type pattern of P-Mad
(Fig. 1J).
Based on previous studies of eggshell patterning, the midline gap in the
tkv pattern corresponds to the highest levels of EGFR activation in
the follicular epithelium, whereas the dorsolateral patches correspond to the
intermediate levels of EGFR activation
(Neuman-Silberberg and Schüpbach,
1994; Goentoro et al.,
2006a). Based on this correlation between the estimated gradient
of EGFR activation and the wild-type tkv pattern, we hypothesized
that high levels of EGFR signaling downregulate tkv, while
intermediate levels of EGFR signaling induce tkv expression. The
midline repression could be due to Pointed, which is activated by high levels
of EGFR signaling and represses EGFR targets
(Fig. 3D)
(Morimoto et al., 1996;
Deng and Bownes, 1997;
Wasserman and Freeman, 1998;
Ward et al., 2006).
This model predicts that a stronger and broader pattern of EGFR activation should increase the distance between the dorsolateral patches of tkv, and that a reduced gradient of EGFR activation can eliminate the dorsolateral patches in the tkv pattern (Fig. 3D). Both these predictions are supported by in situ hybridization analysis of tkv expression in mutants with quantitative variations in EGFR signaling. The distance between the two dorsolateral patches of tkv expression expanded as the level of the oocyte-derived Gurken increased (Fig. 3E). At the same time, the dorsolateral patches of tkv were abolished in the egg chambers with a hypomorphic allele of EGFR (Fig. 3F). The P-Mad pattern closely followed these transitions (Fig. 3G,H), once again demonstrating that Dpp signaling is controlled by the spatial pattern of tkv.
Correlation between the dynamics of Dpp signaling and Br expression
In the next set of experiments, we used Br, a transcription factor
expressed in the cells that form the roof of future dorsal appendages, to
study the patterning effects of Dpp signaling. Br is initially expressed at
low levels throughout the oocyte-associated follicular epithelium; it is then
repressed in the anterior and dorsal midline cells
(Fig. 4A)
(Deng and Bownes, 1997). The
P-Mad domain borders, but does not overlap the Br domain at this stage
(Fig. 4A). At later stages of
oogenesis, Br is expressed at high levels in two dorsolateral patches of the
follicle cells, called the `roof' cells
(Fig. 4B,C). High levels of Br
in the roof cells became clear at stage 10B of oogenesis. At this stage, the
P-Mad domain expanded posteriorly and overlapped the most anterior row of
Br-expressing cells (Fig. 1I
and Fig. 4B). From stage 11 and
onward, the patterns of P-Mad and Br overlapped quite significantly
(Fig. 4C).
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|
). Thus, while the levels of Br protein in the roof cells are
sustained, the expression of br transcript in these cells is
transient, and can be viewed as a pulse in time. We will return to this
difference in our analysis of the connection between Dpp signaling and
br.
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; Dequier et al.,
2001; Chen and Schüpbach,
2006). However, studies of Br pattern in egg chambers with clones
of tkv- and Medea-
(Med-, a co-Smad essential for Dpp signal transduction)
cells concluded that Dpp signaling provides a positive input for Br expression
(Peri and Roth, 2000;
Shravage et al., 2007). Given
these conflicting results and the dynamic character of Br expression, we
revisited the effect of Dpp on Br.
The sign of the effect of Dpp signaling on Br can be deduced from changes
of the Br pattern in response to the local perturbations of the Dpp pathway.
For example, if Dpp acts as a repressive signal, then negative perturbations
of Dpp signaling are expected to lead to ectopic Br expression in the anterior
cells. To test this prediction, we generated the GFP-marked clones of cells
lacking Medea, and examined their effect on the expression pattern of
Br. We found that anterior Med- clones generated
cell-autonomous ectopic Br expression (Fig.
4H-J). We found similar results in experiments with anterior
clones tkv- cells (see Fig. S1 in the supplementary
material) and in the egg chambers expressing tkv-RNAi construct (see
Fig. S2 in the supplementary material)
(Crickmore and Mann, 2006;
Dietzl et al., 2007). Based on
this, we concluded that Dpp signaling represses Br in the anterior follicle
cells. This is consistent with the anticorrelated patterns of Br and P-Mad in
these cells (Fig. 4A,B).
Dpp signaling limits the duration of br expression in the roof cells
In contrast to their clear effect in the anterior of the egg chamber,
Med- and Mad- clones did not affect Br
expression in the roof cells (Fig.
4K-P). Furthermore, we observed no defects in Br expression in the
roof cells in egg chambers where the Dpp pathway was uniformly inhibited by
overexpressing Dad, an inhibitory Smad
(Fig. 5B). The only change in
the Br pattern in this background amounted to its expansion to the anterior
boundary of the follicular epithelium (Fig.
5B). These observations would be consistent with the model in
which the effect of Dpp is repressive. Indeed, removal of repressor in the
region that already expresses Br (roof cells) can only increase the level of
expression, and could not be detected on the background of already strong Br
expression level.
The appearance of P-Mad in the roof cells correlates with the disappearance
of br transcript in this region
(Fig. 4C,G). Based on the
repressive effect of the Dpp pathway in the anterior cells, we hypothesized
that the late (DV) phase of Dpp signaling is responsible for the
downregulation of br transcript in the roof cells. This predicts that
in the absence of Dpp signaling, the transient pulse-like pattern of
br expression in the roof cells should be transformed into a
sustained temporal pattern (Fig.
5A). In agreement with this prediction, we found that in egg
chambers with uniformly inhibited Dpp signaling, br was still
expressed at high levels in the roof cells at stage 11 of oogenesis, when it
is already abolished in the wild type (Fig.
5C and Fig. 4G,
respectively). Furthermore, in this background the br pattern
expanded at the expense of the cells that would normally express rho
and contribute to the floor of dorsal appendages
(Fig. 5D,E)
(Ward et al., 2006). This
change in the two-dimensional arrangement of cell fates led to eggshells with
greatly reduced operculum and deformed dorsal appendages
(Fig. 5F-I). This shows that
that uniform inhibition of Dpp signaling in mid-stages of oogenesis does not
cause a developmental delay, and that the observed changes of br
expression reflect the altered pattern of Dpp signaling. Uniform expression of
tkv-RNAi (Crickmore and Mann,
2006; Dietzl et al.,
2007) led to similar effects: we observed longer persistence of
br in the roof cells and ectopic br in the anterior of the
follicular epithelium, and defects in dorsal eggshell structures (see Fig. S2
in the supplementary material). A significant fraction of tkv-RNAi
eggshells had ectopic dorsal appendages (see Fig. S2 in the supplementary
material), consistent with the model in which br marks the roof of
dorsal appendages (Berg, 2005).
Taken together, these data show that Dpp represses Br in the anterior and
limits the duration of br expression in the roof cells, and that this
mode of regulation is important for proper eggshell patterning.
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). At the same time, the induction of Br in the roof cells is
also dependent on EGFR signaling (Deng and
Bownes, 1997; Atkey et al.,
2006). This suggests that high levels of EGFR signaling repress,
whereas intermediate levels of EGFR activate, Br expression. This model agrees
with the results of our own clonal analysis experiments. Using genetic mosaics
with clones of cell lacking ras, which is essential for EGFR
signaling, we found that EGFR affects Br in a region-specific manner: the
midline clones of ras- cells led to ectopic expression of
Br, while ras- clones in the dorsolateral cells greatly
reduced Br expression (Fig.
6A-D). Taken together with our analysis of the effects of Dpp
signaling on Br (Fig. 4H-P),
these results suggest that the rising phase of br expression in the
roof cells is due to EGFR signaling, whereas its shutdown is due to Dpp
signaling.
Br expression in the roof cells is controlled by a negative-feedback loop
The results of the previous sections suggest that EGFR signaling can induce
both br and its repressor (Dpp signaling) in the roof cells
(Fig. 3D,
Fig. 6E). Two models can be
formulated based on these results. In one model, the expression of br
would be controlled by an incoherent feedforward loop, a network in which the
input induces both the target and its repressor in the roof cells
(Alon, 2007). In this case, the
input is EGFR signaling, the target is br, and its repressor is Dpp
signaling in the roof cells. Alternatively, br expression in the roof
cells could be controlled by a negative-feedback loop, whereby Br, activated
by EGFR signaling, would induce tkv and Dpp signaling, which would
then downregulate br. Note that although both of these networks are
consistent with the pulse-like dynamics of br in the roof cells
(Fig. 3 and
Fig. 5A), only the
negative-feedback network provides a natural way for generating an ordered
induction of br and its repressor (Dpp signaling).
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|
DISCUSSION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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;
Shravage et al., 2007), the
pattern of Dpp signaling in oogenesis is not static, and undergoes a clear
transition from purely AP to DV pattern in late stages of eggshell patterning.
This transition reflects the change in the expression of the type I Dpp
receptor and is conserved in fly species separated by more than 40 million
years of evolution. Second, we show that the early and late patterns of Dpp
signaling control the dynamic pattern of br, a transcription factor
expressed in the roof of future dorsal appendages. While the AP phase of Dpp
signaling represses br in the anterior region of the egg chamber, the
DV phase of Dpp signaling limits the duration of br expression in the
roof cells. Third, we establish that, in addition to being regulated by Dpp,
Br actively controls Dpp signaling, thus regulating its own repression via a
negative-feedback loop.
The Br expression pattern is established by sequential action of feedforward and feedback loops
Our results, together with the previously published data, lead to a new
model for the dynamics of Br expression in the roof cells
(Fig. 8A). Within the framework
of this model, the rising phase of Br expression is due a to an incoherent
feedforward loop, a network in which the input activates both the target and
its repressor (Alon, 2007). In
this case, the feedforward loop, formed by EGFR, Pointed, and Br, determines
the spatial pattern of Br (Fig.
6E). This pattern is then modulated in time by a negative-feedback
that depends on the Br-mediated increase of tkv expression and Dpp
signaling. The feedforward part of the model (outlined in blue) is supported
by the previously published gain- and loss-of-function experiments with
Pointed and EGFR signaling (Morimoto et
al., 1996; Deng and Bownes,
1997; Yamada et al.,
2003), and by our analysis of Br expression in
ras- mosaics (Fig.
6). The negative-feedback loop (outlined in red) is supported by
the correlation of patterns of Br, Tkv, and P-Mad
(Fig. 3), by the previously
published experiments with manipulation of the levels of Dpp
(Deng and Bownes, 1997;
Dequier et al., 2001), by our
analysis of Br protein and br transcript in the Dpp pathway
loss-of-function experiments (Fig.
4H-P, Fig. 5), and
by the effects of br- clones and Br overexpression on
tkv and Dpp signaling (Fig.
7).
Dynamics of two-dimensional patterning in the model
We distinguish four phases in the dynamics of the Br pattern
(Fig. 8B). (1) Low levels of Br
before stage 9 of oogenesis are independent of EGFR signaling and insensitive
to repression by Dpp. (2) Following the formation of the DV gradient of EGFR
activation, Br is repressed in the midline and in the dorsoanterior cells. The
midline repression is due to Pointed, a transcription factor induced by high
levels of EGFR activation in the dorsal midline
(Morimoto et al., 1996;
Deng and Bownes, 1997;
Yamada et al., 2003). The
dorsoanterior repression is due to the early phase of Dpp signaling, which
reflects the anterior secretion of Dpp and uniform expression of Tkv
(Peri and Roth, 2000;
Jekely and Rorth, 2003). (3)
Levels of Br begin to rise in the roof cells. Changes in the Br pattern have
two effects on the spatial pattern of Dpp signaling: higher levels of Br lead
to higher levels of tkv in the roof cells. Second, the dorsoanterior
and midline repression of Br generates a corresponding repression of
tkv. (4) As a result, the anteriorly produced Dpp can diffuse over
the `Tkv-free' area to the roof cells. A combination of the arrival of the
anteriorly produced ligand and a higher level of receptor expression leads to
a higher level of Dpp signaling in the roof cells and subsequent repression of
br. Another layer of regulation is provided by Brk, a transcriptional
repressor of Dpp signaling, which is induced by Gurken and repressed by Dpp
signaling in the dorsal follicle cells. Brk antagonizes the repressive effect
of Dpp in the roof cells until the level of Dpp signaling in the roof cells
becomes high enough to repress Brk expression
(Chen and Schüpbach, 2006;
Shravage et al., 2007).
The network characterized in our study can interact with a number of
previously discovered feedback loops
(Queenan et al., 1997;
Wasserman and Freeman, 1998;
Ghiglione et al., 1999;
Reich et al., 1999;
Peri and Roth, 2000;
Ward et al., 2006). For
instance, Argos, which provides negative-feedback control of EGFR signaling in
the dorsal midline, is a potential target of Dpp signaling
(Queenan et al., 1997;
Wasserman and Freeman, 1998;
Klein et al., 2004). Future
work is required to explore the extent to which this feedback loop, which had
been proposed to affect dorsal midline patterning, interacts with the
mechanism established in this paper.
Supplementary material
Supplementary material for this article is available at
http://dev.biologists.org/cgi/content/full/135/2/343/DC1
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ACKNOWLEDGMENTS |
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Footnotes |
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