Program in Developmental Biology, Weill Graduate School of Medical Sciences at Cornell University and Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA
* Author for correspondence (e-mail: m-baylies{at}ski.mskcc.org)
Accepted 25 November 2004
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SUMMARY |
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Key words: Wingless, Twist, Slouch, Muscle, Mesoderm, Founder cell, Drosophila
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Introduction |
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Less is known about how Wg provides patterning information to a group of
cells in which the target field is neither a uniform epithelium nor contains
the production site of the Wg signal. In vertebrates, for example, Wnts
secreted by the neural tube have been shown to be important in specifying
sclerotome and promoting proper muscle differentiation
(Munsterberg et al., 1995;
Tajbakhsh and Cossu, 1997
).
Likewise in Drosophila, Wg secreted by the ectoderm is essential for
mesoderm development (Baylies and
Michelson, 2001
; Frasch,
1999
). Analysis of wg null embryos reveals that the heart
and particularly, the body wall muscles, either do not form or do not form
normally (Baylies et al., 1995
;
Wu et al., 1995
;
Ranganayakulu et al.,
1996
).
The requirement for Wg signaling has been linked to several steps in
Drosophila larval muscle formation. Body wall muscles arise from
somatic mesoderm that is set aside in the posterior domain of each segment.
The somatic mesoderm is marked by expression of high levels of Twist, a
crucial tissue-specific transcriptional regulator for mesoderm and muscle
development (Bate, 1993;
Borkowski et al., 1995). High Twist levels direct these cells to adopt a body
muscle fate. When Twist levels are reduced in these cells, body muscles fail
to form (Baylies and Bate,
1996
; Castanon et al.,
2001
). Within the region of high Twist expression, 19 pre-muscle
clusters or equivalence groups expressing Lethal of scute (L'sc)
(Carmena et al., 1995
)
subsequently emerge. A single muscle progenitor cell is singled out from each
equivalence group through the combined actions of Notch and Ras signaling
(reviewed by Frasch, 1999
;
Baylies and Michelson, 2001
).
This progenitor cell divides asymmetrically to give two muscle founder cells,
or a muscle founder cell and an adult muscle progenitor cell (Carmena, 1998b;
Ruiz Gomez and Bate, 1997
).
Founder cells then fuse with surrounding fusion-competent cells, attach to
appropriate sites on the epidermis and are properly innervated
(Bate, 1990
;
Bate, 1993
;
Dohrmann et al., 1990
). Wg
acts on the mesoderm to maintain high Twist levels
(Bate and Rushton, 1993
),
initiate L'sc expression (Carmena et al.,
1998a
) and regulate some founder cell identity gene expression
(Baylies et al., 1995
;
Ranganayakulu et al., 1996
;
Wu et al., 1995
). It has been
shown, in one case only, that of the muscle founder identity gene
even-skipped (eve), that the Wg transcriptional effector
DTCF or Pangolin directly binds to the eve muscle enhancer
(Halfon et al., 2000
;
Knirr and Frasch, 2001
).
While the cells of the mesoderm undergo positional rearrangements and cell fate changes, the position and amount of ectodermal Wg remains constant. If Wg is required throughout mesodermal development, how do the cells of the mesoderm interpret the steady flow of the Wg signal correctly and, as a result, respond with activation of different target genes at different times in development? To address this question, we analyzed the requirement for Wg signaling in the specification of muscle founder cells that express the identity gene slouch. In wg mutant embryos, all Slouch-positive founder cell clusters are lost. We now report that Wg regulates each Slouch cluster differently. To specify Slouch-expressing cluster I in the mesodermal hemisegment, Wg signaling is required to maintain high Twist levels. However, to specify Slouch-expressing cluster II in that same hemisegment at a later time, Wg not only needs to maintain high Twist levels, but also needs to provide a second, Twist-independent contribution to activate Slouch expression. Thus, Wg controls the temporal and spatial activation of Slouch expression in the individual clusters through distinct signaling mechanisms. This dual requirement for Wg in specifying cluster II provides a novel insight to how one signaling pathway can be used repeatedly throughout development to impart patterning information within a target field.
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Materials and methods |
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Temperature-shift experiments were carried out as follows: embryos carrying
a hypomorphic allele of wg (wgIL114/CyO,ftz-lacZ)
were kept in laying pots at 18°C (permissive temperature), and were
synchronized by changing apple juice plates every hour. After 15 hours (very
late stage 11), 13 hours (late stage 11) or 12 hours (mid-stage 11) at
18°C, embryos were dechorionated and either immediately fixed, or shifted
to 25°C (nonpermissive temperature) for another 2-3 hours to develop until
very late stage 11. Embryos were then fixed according to standard protocols
(Rushton et al., 1995). In a
parallel experiment, embryos were raised at 25°C for 8 hours (very late
stage 11), then fixed as usual. Slouch expression was then examined using the
antibody staining protocol described below.
Immunocytochemistry
Immunocytochemistry in embryos (Rushton
et al., 1995) was performed using antibodies to S59 (Slouch;
1:200) (Baylies et al., 1995
),
ß-galactosidase (1:1000; mouse, Promega), Twist (1:5000; provided by S.
Roth), and biotinylated secondary antibodies (Jackson Immunoresearch) used in
combination with Vector Elite ABC kit (Vector Laboratories). Specimens were
embedded in Araldite. Images were captured using an Axiocam with accompanying
software (Zeiss). Different focal planes were combined into one picture using
Adobe Photoshop software. Immunofluorescent staining was carried out using
anti-S59 (1:100) or anti-Krüppel (1:500) (provided by J. Reinitz). Slouch
was visualized using a secondary antibody conjugated to horseradish peroxidase
(Vector Laboratories), followed by FITC tyramide (Vector Laboratories). Kr was
visualized using a biotinylated secondary followed by Cy3 conjugated to
streptavidin (Vector Laboratories). Immunofluorescent signals in
co-localization studies were analyzed using a Zeiss LSM 510 confocal
microscope.
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Results |
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Expression of lacZ driven by wg promoter elements in
wild-type embryos revealed that, during the differentiation of the Slouch
founder cells, Wg-producing cells in the ectoderm directly overlie cII
Slouch-expressing cells but not those of cI
(Fig. 1E). Wg expression in the
embryo changes in two important ways over the course of mesoderm development.
Wg protein is initially detected symmetrically on either side of the
Wg-expressing cells. Then, the protein expression becomes restricted to the
anterior side after stage 9 when the mesoderm begins the allocation of cells
to different fates. Also, during stage 11, the continuous ectodermal stripe of
Wg expression breaks into two regions, one dorsal and one ventral, leaving a
small gap laterally (Gonzalez et al.,
1991). The Slouch-positive founders cells in cI and cII arise
ventrally and are therefore exposed to a continuous supply of Wg. However,
because of its position relative to that of the constant source of Wg from
overlying ectodermal cells, cII is likely to receive higher levels of Wg.
Therefore, we hypothesized that cII required a different amount of Wg to be
patterned, and that this difference is instructive in specifying the identity
of cII versus cI and hence the muscles that arise from them.
Partial loss of function in the Wingless pathway leads to loss of Cluster II but not Cluster I
To test whether cII required an increased level of Wg signaling, we
analyzed embryos in which Wg signaling was reduced. Two assays were used to
determine cI and cII identity in these mutant backgrounds: morphology (that
is, position relative to Wg-insensitive Slouch-positive central nervous system
cells) and co-expression of a second founder cell identity gene,
Krüppel (Kr). In wild-type embryos, cII always aligned
with the Slouch-positive central nervous system cells, while cI was located in
the mesoderm just posterior to these cells
(Fig. 2A,A'). Kr had been
shown to co-localize with Slouch in cII but not cI
(Fig. 2A'')
(Ruiz-Gomez et al., 1997). We
manipulated Wg levels using different alleles of genes in the Wg pathway and
reagents that altered Wg signal transduction, and tested these embryos for
alterations in Slouch cI and cII.
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|
Consistent with the morphological studies described above, confocal microscopy studies predominantly showed a failure of Kr to co-localize with Slouch, indicating that the vast majority of the Slouch clusters that did appear in the embryos carrying the different wg alleles were cI and not cII (Fig. 2B'', C''; Table 1; data not shown). Thus, from the analysis of embryos carrying different wg alleles, we concluded that Slouch cII requires more Wg than Slouch cI.
This differential sensitivity of cII was confirmed by overexpressing a
dominant-negative form of the Wg transcriptional effector dTCF/Pangolin
(NTcf) (van de Wetering et al.,
1997
). Pan-mesodermal expression of this construct, which is
missing the Armadillo binding domain, gave a weak wg phenotype:
Slouch cI was always present whereas cII was always affected
(Fig. 2D,E;
Table 1). Increasing the
expression of this construct by using two copies of the pan-mesodermal GAL4
driver again led to a complete loss of cII, and, in addition, cI was missing
in 3% of hemisegments (Fig. 2E;
Table 1). It could be argued
that the ability of UAS
NTcf to repress Slouch cII but not cI completely
was due to the delay of the GAL4-UAS system, or that sufficient levels of the
dominant-negative Tcf protein had not accumulated in time to block formation
of Slouch cI. However, we believe that this is not the case, as
dominant-negative Tcf does affect other mesodermal targets such as L'sc and
Eve at late stage 10 (A. Carmena, unpublished). Taken together, in situations
in which Wg signaling is reduced but not completely eliminated, cII is
preferentially lost.
Gain of function in the Wg pathway increases Slouch cluster II
Given that cII showed a greater response to reduced Wg signaling, we next
investigated whether cII was also more responsive to increased levels of Wg
signaling. The GAL4/UAS system was used to ectopically express Wg throughout
the mesoderm using the twist (twi)GAL4 driver
(Brand and Perrimon, 1993;
Baylies and Bate, 1996
). When
we expressed Wg throughout the mesoderm, cII was significantly expanded in all
hemisegments, while cI always retained its normal size
(Fig. 3A,B,G;
Table 1). While cII size
enlarged reproducibly in response to increased Wg, the number of cells per
cluster varied from hemisegment to hemisegment (5-15 cells, mode=12 cells
versus 4 cells in wild-type). No correlation could be drawn between Wg levels
and the number of cells in cII. In addition, we found no evidence that early
exposure to higher Wg amounts leads to earlier Slouch activation in cII, as
the onset of Slouch cII expression was the same as that found in wild-type
embryos. To reinforce that this effect was mediated by the Wg signal
transduction pathway autonomously in the mesoderm, an activated form of
Armadillo, UASarms10, was expressed throughout the mesoderm. Once
again, cII was significantly expanded in all hemisegments (100%), while cI
remained at wild-type size (Fig.
3C,G; Table 1).
These data indicated that cII was indeed more responsive to increased Wg
signaling and that the effects on cII were mediated by the classical Wg
pathway, at least through the level of Armadillo.
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The specific effect on Slouch cII with loss and gain of Wg signaling was suggestive of a differential requirement of the two clusters for Wg signaling. We could not, however, rule out the formal possibility that cI had not yet shown a response to increased Wg simply because we had not supplied enough Wg to the mesoderm under our experimental conditions. To rule out this possibility, the level of Wg supplied to the mesoderm was increased in two ways. First, the dose of the pan-mesodermal GAL4 driver was increased from one to two copies to drive Wg expression (Fig. 3E,G; Table 1). Wg overexpression in this manner specifically expanded Slouch cII while cI remained at wildtype size. This suggested that a factor other than Wg levels limits cI size. Interestingly, the increased Wg levels obtained using two copies of the GAL4 driver did not expand cII further than that observed using one copy, suggesting an upper limit of Wg responsiveness. Overexpression of an activated Armadillo construct under the same conditions had identical results (Fig. 3G; Table 1 and data not shown).
Second, we tested whether the combination of increased levels and increased length of time that the mesoderm was exposed to Wg might now affect cI as well as cII. We overexpressed Wg using flies that carried two different GAL4 drivers (twiGAL4; Dmef2GAL4), which led to maintained, high levels of mesodermal expression throughout embryogenesis. Ectopic Wg expressed in this manner led to a specific increase in cII size, with no notable increase in the size of cI (Fig. 3F,G; Table 1). Likewise, no additional increase in cII size was noted beyond what was seen under previous conditions. Overexpression of activated Armadillo similarly caused an increase in cII without changing cI, further supporting the assertion that neither the amount nor the length of time exposed to Wg signaling can alter Slouch cI (Fig. 3G, Table 1, data not shown). In addition, despite increased amounts and time of Wg signaling, no change in the onset of Slouch expression was detected. Moreover, these data suggested that neither parameter could further affect the size of Slouch cII. Thus, only a limited number of cells can respond to the Wg signal and increases in amount or time of exposure cannot further expand this domain. Considering these data together, we favor the conclusion that, although both ventral clusters require Wg for their specification, cII displays an increased sensitivity to Wg levels.
Wingless sets up a region competent to express Slouch and is required later to specify the fate of cluster II
We have shown that, although both Slouch cI and cII require Wg, cII is more
sensitive to Wg signaling than cI. We noted that cII arises directly under the
ectoderm cells that produce Wg. We also observed that cI appears in the
mesoderm at early stage 11 whereas cII appears at late stage 11, and that
these two clusters are not related by lineage. Moreover, providing ectopic,
high levels of Wg does not cause an earlier activation of Slouch in the
clusters, suggesting that the accumulation of Wg over time cannot explain
Slouch expression in cI and cII. Taking all this information together, two
models can explain our observations: (1) Slouch cII cells simply need a
greater amount of Wg signaling compared with Slouch cI cells; or (2) since the
clusters arise at different times, Slouch cII requires two sequential Wg
signaling events, whereas Slouch cI requires a single dose of Wg signaling. To
test whether the contribution of Wg to Slouch cluster fate was temporally
separable, we examined Slouch expression in two genetic backgrounds: (1)
embryos carrying null alleles of hedgehog (hh21,
hhAC and hh8) that do not maintain Wg
expression past early stage 11 (DiNardo et
al., 1994); and (2) embryos carrying the wg
temperature-sensitive allele, wgIL114, which have been
shifted to non-permissive temperatures at different points in Slouch cluster
development (Fig. 4).
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We also performed temperature-shift experiments with embryos carrying the
temperature-sensitive allele of wg, wgIL1l4
(DiNardo et al., 1988).
Embryos homozygous for this allele and raised at the permissive temperature
throughout development showed a wildtype phenotype both in the ectoderm and
mesoderm (Bejsovec and Martinez Arias,
1991
) (Fig. 4C,G;
Table 1). By contrast,
wgILll4 embryos raised at the non-permissive temperature
showed a wg null phenotype both for epidermis
(Bejsovec and Martinez Arias,
1991
) and for mesoderm. Specifically, neither Slouch cI nor cII
are specified (Fig. 4D,G;
Table 1). We next removed
wg function selectively during development by shifting from the
permissive to the non-permissive temperature at mid-stage 11 (12 hours AEL)
and at late stage 11 (13 hours AEL). Embryos shifted at the later timepoint
showed expression of Slouch cI in all hemisegments and an occasional loss of
Slouch cII (present in 66% of mutant hemisegments;
Fig. 4E,G;
Table 1). By contrast, embryos
shifted at mid-stage 11 displayed a significant increase in the number of
hemisegments in which cII was lost (present in 0% of mutant hemisegments); cI
was present in all hemisegments analyzed
(Fig. 4F,G; Table 1). Altogether our data
suggested that specification of Slouch cII requires a temporally separable
input of Wg signaling.
Wg-dependent Twist expression is sufficient for Slouch cI but not cII
In wg mutant embryos, Twist expression is initiated correctly, but
high levels of Twist are reduced by mid to late stage 11, the period during
which the Slouch clusters appear (Bate and
Rushton 1993). We hypothesized that to form cI, Wg needed only to
activate Twist, as Wg was required first to sustain high Twist levels, and all
founder cells, including the Slouch-positive ventral clusters, are derived
from the high Twist domain (Baylies and
Bate, 1996
; Carmena et al.,
1995
). However, to specify the identity of cII, we proposed that
Wg must provide an additional, Twist-independent signaling event. This does
not rule out the possibility that other signals and transcriptional regulators
such as l'sc (Carmena et al.,
1995
) and ladybird
(Knirr et al., 1999
)
contribute to cI identity, but simply, that Wg was not required after the
initial input to Twist expression for cI. Additional support for this idea
comes from our studies of the different wg alleles; embryos in which
cI was present but cII was missing had wild-type Twist levels
(Fig. 2B,C; data not
shown).
To test this hypothesis, we expressed Twist throughout the mesoderm in wg null mutant embryos (Fig. 5A,B). When we examined these embryos, we saw rescue of some Slouch expression (Fig. 5C,D,E; Table 1), in contrast to the complete loss of mesodermal Slouch expression seen in wgCX4 embryos. To determine the identity of the rescued Slouch cells, both morphology and the co-localization of Kr and Slouch were assayed. When Twist was expressed in the mesoderm of wg mutant embryos, the ventral Slouch expression did not co-localize with Kr and did not align with the Slouch-positive nervous system cells, indicating that the cells rescued in these mutant embryos were not cII (Fig. 5D',D''; Table 1). We had no additional independent marker for cI. Thus, we were unable to determine unequivocally that the identity of the rescued Slouch-positive cells represented cI; however, the ventral position of these cells and the lack of Kr staining would suggest a cI identity. Increasing Twist levels by using multiple copies of the GAL4 driver or different GAL4 drivers, led to a mild increase in cI appearance but not in cII (Fig. 5E; Table 1). These data indicate that Wg uses two distinct mechanisms to pattern these two clusters and direct the expression of Slouch: in the case of Slouch cI, Wg needs only to maintain high Twist levels, whereas the fate of Slouch cII additionally requires a temporally distinct input from Wg that is Twist-independent (Fig. 6).
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Discussion |
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It has previously been shown that wg mutants fail to maintain high
levels of Twist (Bate, 1993).
Overexpression of Twist led to expanded somatic mesodermal fates at the
expense of other mesodermal fates, such as heart and gut muscle. Conversely,
decreasing Twist levels led to a reduction in somatic mesodermal fate, while
heart and gut muscle remained largely unaffected
(Baylies and Bate, 1996
). Our
findings underscore the importance of high Twist levels for the proper
implementation of somatic muscle fate. Because loss of high Twist levels leads
to loss of muscle founder cells, including all Slouch-positive clusters of
founder cells, it has always appeared that each Slouch cluster required the
same amount of Wg signal (relayed through Twist) to assume its particular
fate. In this study, we uncoupled the requirement for Wg in maintaining high
Twist levels from the later role of Wg in specifying cII fate. The fact that
Twist specifically rescues Slouch cI in a wg mutant background
suggests that Slouch cII requires an additional, Twist-independent
contribution from Wg for proper patterning. Consistent with these results, we
found wg hypomorphs that provided sufficient signaling to maintain
high Twist levels during early mesoderm development and therefore pattern cI,
but that did not pattern cII. Temperature-shift experiments using wg
temperature-sensitive alleles have shown that Slouch cII specification and
engrailed expression in the ectoderm required Wg expression at later
stages of embryonic development (Dierick
and Bejsovec, 1998
; DiNardo et
al., 1994
; Owen,
1994
) (this study). Thus, the absence of Slouch cII in the
different wg alleles, in hh mutant embryos and in a Twist
rescued wg mutant embryo, all suggest that proper patterning requires
not only an earlier Wg-dependent regulation of Twist, but also an additional
Wg contribution to specify its identity.
Our manipulations of Wg signaling also revealed two additional aspects of
Wg signaling to the mesoderm. First, we found that the mesoderm, in general,
has a different threshold for Wg signaling when compared with the ectoderm.
Conditions that completely rescue the ventral ectoderm and epidermis
(wgPE6 at the permissive temperature) failed to completely
rescue the mesoderm. Second, we find that different mesodermal targets respond
differently to Wg signaling. For example, we find that expression of the
NTcf had mild effects on Twist but significant effects on Slouch cII.
Although we predict that TCF binds slouch regulatory regions
directly, we have found that Wg regulates Twist both directly through TCF and
indirectly through the pair-rule gene sloppy-paired (V.T.C. and
M.K.B., unpublished) (Lee and Frasch,
2000
). Whether or not the difference in Wg regulation of
twist and slouch is due to the structure of the regulatory
regions, additional factors that integrate on these promoters in these
contexts and the activity of the Arm/dTCF complex remains to be uncovered.
Our study also underscores the contribution that other factors make to
position the Slouch clusters: ectopic Wg expression in the mesoderm does not
produce uniform Slouch expression (Baylies
et al., 1995; Brennan et al.,
1999
). This aspect of Wg signaling is reflected in other tissues
such as the epidermis (Sampedro and
Guerrero, 1991
). Indeed, we were unable to further enlarge the
size of Slouch cII beyond that seen when we initially increased Wg signaling
(Fig. 3). This suggests a
prepatterning mechanism, perhaps involving the activity of the pair-rule genes
that have been shown to be responsible for segmentation of the mesoderm
(Azpiazu et al., 1996
;
Riechmann, 1997
), as well as
the integration of other signal transduction pathways, such as EGF/FGF and
Notch signaling (Brennan et al.,
1999
; Carmena et al.,
2002
; Carmena,
1998a
). Our data suggest that Wg signaling then works on this
prepattern to regulate the domain of Slouch expression.
The effect of Wg that we have described on muscle patterning is similar to
that described for even-skipped muscle progenitor specification; that
is, Wg signaling (in collaboration with such signals as Decapentaplegic) is
first required to set up a region of `competence' through activation of
mesoderm-specific factors such as Twist and Tinman. Wg then later cooperates
with these intrinsic factors to induce the expression of even-skipped
in dorsal muscle progenitors (Halfon et
al., 2000), much as we would suggest for Slouch cII. However, our
observations suggest an important variation of Wg signaling in mesodermal
patterning. In the case of Slouch patterning, Wg creates temporal as well as
spatial diversity, while in patterning eve it only acts temporally.
Wg signaling contributes to the expression of Slouch in its two discrete
ventral patches by two distinctive mechanisms: through the regulation of an
upstream transcription regulator (Twist), which is sufficient for one domain
of expression; and through the cooperation of this factor with a second,
temporally distinct Wg input for the second domain of expression. The
expression of the same gene but at two different times and places, through two
Wg-dependent means, gives insight into how an organism may generate diverse
tissues in response to the same signal.
A new molecular look for morphogens?
Work carried out in the wing imaginal disc suggested that Wg acts as a
morphogen. In this tissue, Wg protein could be visualized in a graded
distribution and it appeared to activate multiple target genes directly, in a
concentration-dependent manner (Strigini
and Cohen, 2000; Zecca et al.,
1996
). Based on these criteria, Wg was labeled as a classical
morphogen. However, careful inspection of the molecular mechanisms underlying
Wg activation of both short- and long-range targets in the wing have revealed
that the pattern of Wg expression changes during wing imaginal disc
development, and that Wg collaborates with other pathways to set up the
expression of these genes. These studies have cast doubt on whether Wg is a
true morphogen in this tissue (Martinez
Arias, 2003
).
Our work, investigating the molecular mechanisms that govern patterning of the embryonic mesoderm, similarly suggests that Wg does not act on Slouch clusters I and II as a classical morphogen. We discovered that Wg does not activate cI directly, but that, instead, it maintains high levels of Twist, which sets up a somatic mesodermal competency domain that is sufficient to create cI. Additional Wg is then required later to pattern cII. It can be argued that Wg acts as a morphogen to regulate Twist expression (at low levels), and then to control Slouch expression (at high levels) within cells of cII. However, the precise regulation and dependence of Slouch clusters I and II on Wg within both the dorsoventral and anteroposterior axes suggest that there must be additional patterning information available to properly place these two cell types. As more putative morphogens are held up to the lens of molecular biology, it will be interesting to see whether there are unexpected, new twists in the molecular underpinnings of morphogens.
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ACKNOWLEDGMENTS |
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