1 Laboratoire de Génétique et Physiologie du Développement,
IBDM, CNRS, Université de la méditerranée, Parc
Scientifique de Luminy, Case 907, 13288, Marseille Cedex 09, France
2 Biozentrum der Universität Basel, Klingelbergstrasse 70, CH-4056 Basel,
Switzerland
3 University of Cambridge, Department of Zoology, Downing Street, Cambridge CB2
3EJ, UK
4 Centro Andaluz de Biología del Desarrollo, Universidad Pablo de
Olavide, Carretera de Utrera, Km 1, Seville, 41013, Spain
* Author for correspondence (e-mail: graba{at}ibdm.univ-mrs.fr)
Accepted 4 May 2005
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SUMMARY |
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Key words: Hox, Signalling, Organogenesis, Drosophila
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Introduction |
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The definition and fate of metameric units constitute a paradigm to
understand the function of Hox and intrasegmental signalling molecules
(DiNardo et al., 1994;
Lewis, 1978
;
Martinez-Arias and Lawrence,
1985
). Functional interactions between Hox and signalling
activities have been reported in a number of developmental processes
(Chen et al., 2004
;
Dubrulle et al., 2001
;
Gieseler et al., 2001
;
Grienenberger et al., 2003
;
Immergluck et al., 1990
;
Joulia et al., 2005
;
Knosp et al., 2004
;
Marty et al., 2001
;
Panganiban et al., 1990
;
Ponzielli et al., 2002
;
Reuter et al., 1990
;
Zakany et al., 2001
). Two
studies have linked Hox and signalling molecules within the context of segment
morphogenesis. The first concerns the regulation of Serrate, and
ultimately that of rho, by the Hox proteins Ultrabithorax (Ubx) and
Abdominal-A (AbdA) in the ventral ectoderm, to specify aspects of the
abdominal denticle pattern (Wiellette and
McGinnis, 1999
). The second concerns the regulation of
rho by AbdA in the lateral ectoderm of abdominal segments to allow
oenocyte development (Brodu et al.,
2002
). Although these studies have provided important insights
into how Hox proteins distinguish abdominal segments from more anterior ones,
much remains to be learned about how Hox and signalling factors interact to
specify segment-specific morphogenesis.
We have investigated how cells respond to axial and intrasegmental
positional inputs during posterior spiracle morphogenesis and how Hox and
signalling activities cooperate to control the formation of a segment-specific
structure. The posterior spiracle develops in the eighth abdominal segment
(A8) from an epithelial sheet of ectodermal cells that subdivides into two
populations. The inner cells, that give rise to the spiracular chamber,
invaginate and eventually form an internal tube, the filzkörper, which
constitutes the opening of the gas exchange system of first instar larvae
(Hu and Castelli-Gair, 1999).
The surrounding cells undergo rearrangements, in a manner similar to the
process of convergent extension (Warga and
Kimmel, 1990
), to form the stigmatophore, the external part of the
organ in which the filzkörper tube is located.
The Hox gene Abdominal-B (AbdB) initiates the
developmental program of posterior spiracle formation
(Hu and Castelli-Gair, 1999).
This program is formed by two genetic modules that control morphogenesis of
the spiracular chamber and stigmatophore, respectively. Each module comprises
primary targets, the expression of which does not depend on the activity of
the others: cut, empty spiracles (ems), Klumpfuss
and nubbin for spiracular chamber cells; and spalt
(sal) for stigmatophore cells. Enhancers that recapitulate expression
in the posterior spiracle have been identified for cut
(Jack and DeLotto, 1995
) and
ems (Jones and McGinnis,
1993
), suggesting that these targets may be directly controlled by
the Hox protein. These genes encode transcription factors that activate
secondary targets, which also encode transcription factors. However, we lack
an understanding of how AbdB or genes acting downstream cooperate with other
developmental cues to promote posterior spiracle morphogenesis. We have found
that posterior spiracle morphogenesis relies on a dynamic genetic network made
of multiple Hox/signalling interplays, and that AbdB plays a fundamental role
in reorganising intrasegmental positional cues during organogenesis.
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Materials and methods |
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Cuticule preparations, immunostaining and whole-mount in situ hybridisation
Embryo collection, cuticule preparations, in situ hybridisation and
immunodetection of whole embryos were performed according to standard
procedures. The anti-AbdB, anti-Cut and anti-En antibodies were obtained from
the Developmental Study Hybridoma Bank (DSHB, Iowa University) and used at a
1:5 dilution. The rabbit anti-Spalt primary antibody was a gift from Reinhart
Shuh (Kuhnlein et al., 1994)
and used at a 1:50 dilution. The rabbit anti-Mirror antibody was provided by
H. McNeill and used at a 1:1000 dilution. The anti-ß-Galactosidase
(Cappel) and anti-GFP (Promega) antibodies were used at a 1:500 dilution.
Digoxigenin RNA-labelled probes were generated according to the manufacturer's
protocol (Boehringer-Manheim) from hh, wg, rho and ems cDNAs
cloned in Bluescript (Stratagene). Secondary antibodies were either coupled to
alkaline phosphatase, biotin or peroxidase (Jackson ImmunoResearch
Laboratories), or conjugated to Alexa-488 or Alexa-594 (Molecular Probes), and
used at suppliers recommended dilutions. When needed, the signal was amplified
with the aid of a Tyramide Signal Amplification kit (NEN Life Sciences).
Embryos stained with fluorochromes were mounted in Vectashield (Vector
Laboratories) for observation under a confocal microscope (Leica TCS SP2 or
LSM 510 Zeiss). Images were processed with the Leica TSC NT 1.6, Zeiss LSM5
Image Browser and Adobe Photoshop 7.0 programmes. The Imaris software
(Bitplane) was used for 3D reconstruction with the Shadow Projection
function.
Thermosensitive experiments
The temporal requirement of Wg, Hh and Egfr signalling for posterior
spiracle morphogenesis was assessed using temperature-sensitive alleles of
wg (wgIL114), hh
(hhts2) and Egfr (Egfrtsla).
Embryos were collected over a 1 hour period at 18°C and left to develop at
the same permissive temperature from 3 to 10 hours before shifting them to
29°C, a restrictive temperature for all alleles. Cuticles were prepared 36
hours after egg laying.
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Results |
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Specification of posterior spiracle primordia occurs at early stage 11
(Fig. 1A). The primordia can
then be recognised by Cut expression in spiracular chamber cells and by Sal,
the homogenous expression of which in A8 becomes restricted dorsally to
stigmatophore cells that form a crescent surrounding Cut-positive cells
(Fig. 1A'). From
mid-stage 11, wg and rho adopt in the dorsal ectoderm
expression patterns specific to A8, with wg transcribed in two cells
only (Fig. 1J) and rho
in a second cell cluster, dorsal and posterior to the tracheal placode
(Fig. 1P). To localise
wg- and rho-expressing cells with regards to stigmatophore
and spiracular chamber cells, co-labelling experiments for wg or
rho transcripts and for Cut or Sal proteins were performed: the two
wg cells lie between Cut- and Sal-positive cells
(Fig. 1K,L); the second cell
cluster expressing rho in A8 also expresses Cut but not Sal
(Fig. 1Q,R). This cluster is
likely to produce the Egf ligand required for posterior spiracle development,
as mutations that alleviate rho expression in the tracheal placodes
(Boube et al., 2000;
Isaac and Andrew, 1996
;
Llimargas and Casanova, 1997
)
do not abolish spiracles formation (Hu and
Castelli-Gair, 1999
). At mid-stage 11, the hh pattern in
A8, along a stripe lying posterior and adjacent to the spiracular chamber
(Fig. 1E) and overlapping
stigmatophore presumptive cells (Fig.
1F), resembles expression in other abdominal segments
(Fig. 1D). Analyses at later
stages (Fig. 1B) indicate that
the relationships between posterior spiracle cells
(Fig. 1B') and
hh (Fig. 1G,H),
wg (Fig. 1M,N) and
rho (Fig. 1S,T)
patterns are maintained.
Wg, Hh and Egfr signalling are required for posterior spiracle formation after primordia specification
Null mutations of wg, hh or Egfr result in the absence of
posterior spiracles (Fig.
2C,E,G). The strong cuticular defects observed raise the
possibility that the phenotypes result indirectly from early loss of segment
polarity. Removing the Wg, Hh or Egfr signals from 5-8 hours of development
using thermosensitive alleles causes strong segment polarity defects but
allows filzkörpers (Fig.
2D), stigmatophores (Fig.
2F) or even complete posterior spiracles
(Fig. 2H) to form. Thus,
spiracular chamber and stigmatophore can develop in embryos that have
pronounced segment polarity defects.
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Wg, Hh and Egfr signalling in spiracular chamber and stigmatophore cells is required for posterior spiracle organogenesis
We next investigated the role of Wg, Hh and Egfr signalling pathways in
posterior spiracle organogenesis (i.e. after the specification of presumptive
territories). Co-labelling experiments performed on embryos expressing GFP
driven by ems-Gal4 or by sal-Gal4 indicate that whereas Cut
and Sal are already expressed at early stage 11
(Fig. 4A,C), GFP is detected
from late stage 11 only (Fig.
4B,D). These two drivers, which promote expression approximately 1
hour after primordia specification, were used to express DN molecules for each
pathway, counteracting Wg (DN-TCF), Egfr (DN-Egfr) or Hh [DN-Cubitus
interuptus (Ci)] signalling from that time on. Blocking either pathway in
spiracular chamber cells does not perturb stigmatophore morphogenesis, but
specifically leads to the loss of differentiated filzkörpers
(Fig. 4E-G). Conversely,
blockade in stigmatophore cells provokes in each case its flattening, while
differentiated filzkörpers do form
(Fig. 4H-J).
|
AbdB and Hh remodel wg and rho expression in A8 dorsal ectoderm at mid-stage 11
A8-specific modulation of rho and wg patterns at
mid-stage 11 suggests a regulation by AbdB. In AbdB mutants,
rho expression in the spiracle-specific cell cluster is lost
(Fig. 6A), and wg
transcription does not evolve towards an A8-specific pattern
(Fig. 6B). In embryos
expressing AbdB ubiquitously, ectopic posterior spiracle formation in the
trunk can be identified as ectopic sites of Cut accumulation. In such embryos,
rho and wg are induced in trunk segments following patterns
that resemble their expression in A8: rho in a cluster that overlaps
the Cut domain (Fig. 6D), and
wg in few cells abutting ectopic Cut-positive cells
(Fig. 6E). These
transcriptional responses to loss and gain of function of AbdB indicate that
the Hox protein controls the A8-specific expression patterns of wg
and rho. The lines gene (lin), which is known to be
required for Cut and Sal activation by AbdB
(Castelli-Gair, 1998), also
controls wg and rho patterns respecification (see Fig. S1 in
the supplementary material).
In contrast to wg and rho, hh does not adopt an A8-specific expression pattern at mid-stage 11 (Fig. 1D). At that stage, hh expression pattern is not affected upon AbdB mutation (Fig. 6C). The hh stripe in A8 lies posterior and adjacent to spiracular chamber cells and overlaps stigmatophore cells (Fig. 1E,F), suggesting that Hh signalling may participate in the regulation of rho and wg transcription by AbdB. In support of this, we found that the AbdB-dependent aspects of rho and wg transcription patterns are missing in hh mutant embryos (Fig. 6F,G). Thus, inputs from both Hh and AbdB are required to remodel Wg and Egfr signalling in A8.
The dependence of wg and rho A8 expression patterns on Hh, and the loss of ems expression in wg and rho but not in hh mutants, suggest that transcription of ems requires Wg and Egfr signalling prior to wg and rho pattern respecification by AbdB and Hh. To explore this point further, we comparatively analysed the time course of ems, wg and rho expression. Embryos bearing an ems-lacZ construct stained for ß-Gal and for wg or rho transcripts show that ems expression precedes wg pattern respecification (Fig. 6H,I), and occurs at the same time as rho acquires an A8-specific pattern (Fig. 6J,K). Importantly, we never detected A8-specific rho clusters before the onset of ems expression. Thus, ems transcription starts before wg and at the same time as rho pattern respecification, supporting that signalling by Wg and Egfr is required prior to mid-stage 11. These observations also indicate that respecification of the wg pattern occurs slightly later than that of rho, which could not been concluded from changes in embryo morphology.
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AbdB controls A8-specific expression of hh at stage 12 and de novo expression of engrailed at stage 13
The expression of the posterior compartment selector gene
engrailed (en) until stage 12 follows a striped pattern
identical in all trunk segments (Fig.
8B). Later on, En adopts a pattern that is specific to A8: it is
no longer detected in the ventral part of the segment; and, dorsally, the En
stripe has turned to a circle of cells that surround the future posterior
spiracle opening (Fig. 8C) and
express the stigmatophore marker Sal (not shown). The transition from a
striped to a circular pattern depends on AbdB (not shown)
(Kuhn et al., 1992). This
transition could result either from a migration of en posterior cells
towards the anterior, or from transcriptional initiation in cells that were
not expressing en before stage 12, and that can therefore be defined
as anterior compartment cells.
To distinguish between the two possibilities, en-Gal4/UAS-lacZ embryos were simultaneously stained with anti ß-Gal and anti-En antibodies. If circle formation results from cell migration, one would expect ß-Gal and En to be simultaneously detected in all cells of the circle as the two proteins are already co-expressed in the posterior compartment stripe earlier on. Conversely, if the circle results from de novo expression, one would expect anterior cells in the circle to express En before ß-Gal, as ß-Gal production requires two rounds of transcription/translation compared with one for En (Fig. 8A). We found that cells from the anterior part of the circle express En but not ß-Gal in stage 13 embryos (Fig. 8C), which demonstrates that de novo expression of En occurs in anterior compartment cells. Further supporting En expression in anterior compartment cells, we found that precursors of anterior spiracle hairs that do not express En at stage 12 do so at stage 13 (see Fig. S3 in the supplementary material). En function in A8 is essential for posterior spiracle development, as stigmatophores do not form in en mutants (Fig. 8D), and are restored if En is provided in stigmatophore cells (Fig. 8E).
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Discussion |
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The second phase, which immediately follows primordia specification, concerns the regulation of AbdB target genes activated slightly later. Inputs from the Hox protein and the Wg and Egfr pathways are then simultaneously needed, as seen for transcriptional initiation of the ems downstream target. This function of Wg and Egfr signalling precedes and does not require the reallocation of signalling sources in A8-specific patterns, as impairing A8-specific expression of wg and rho by loss of hh signalling does not affect ems expression. Within the third phase, AbdB and Hh activities converge to reset wg and rho expression patterns. The three phases take place in a narrow time window, less than 1 hour during stage 11, and could only be distinguished by studying the functional requirements of Wg, Hh and Egfr for transcriptional regulation in the posterior spiracle.
We refer the fourth phase as an organogenetic phase. Data obtained using DN variants to inhibit the pathways in cells already committed to stigmatophore or filzkörper fates, indicate that Wg, Egfr and Hh pathways are required for organ formation after specification and early patterning of the primordia. Their roles are then to maintain AbdB downstream targets expression in posterior spiracle cells as development proceeds, as shown for Cut and Sal at stage 13.
Hox control of morphogenesis: conferring axial properties to intrasegmental patterning cues
A salient feature of AbdB function during posterior spiracle development is
to relocate Wg and Egfr signalling sources in the dorsal ectoderm at mid-stage
11. wg and rho then adopt expression patterns that differ
from expressions in other abdominal segments, conferring axial properties
unique to A8 to otherwise segmentally reiterated patterning cues. Resetting Wg
and Egfr signalling sources into restricted territories is of functional
importance for organogenesis, as revealed by the morphological defects that
result from the delivery of Wg or SpiS signals in all spiracular
chamber or stigmatophore cells after the specification phase. During stage 12,
AbdB also relocates the Hh signalling source by inducing En-independent
expression of hh in the dorsal ectoderm. Thus, later than Wg and Egfr
signalling, the Hh signal also acquires properties unique to A8. In generating
this pattern, AbdB plays a fundamental role in uncoupling hh
transcription from En activity, providing a context that prevents anterior
compartment En-positive cells to turn on hh transcription (compare
Fig. 8C with
Fig. 1G,H), and that allows
hh expression in the absence of En in other cells
(Fig. 8I). Slightly later, at
stage 13, AbdB modifies the expression of the posterior selector gene
en, initiating de novo transcription in anterior compartment cells.
In these cells, En fulfils different regulatory functions than in posterior
cells, as discussed above for hh regulation. Changes in En expression
and function can be interpreted as a requisite to loosen AP polarity in A8 and
gain circular coordinates required for stigmatophore formation
AbdB function during posterior spiracle morphogenesis suggests that
Hox-induced reorganisation of positional information may be central for
shaping cellular fields during organogenesis. A recent report on limb
morphogenesis supports this view: early colinear restriction of 5' Hoxd
genes provides initial asymmetry to the nascent limb bud and controls
posterior expression of Sonic Hedgehog at the zone of polarising activity
(Zakany et al., 2004).
Subsequent to this initial phase, the expression of the same 5' Hoxd
genes acquires a reverse colinear polarity that is necessary for generating
the distal limb structures. Thus, in this extreme case, Hox-controlled
reorganisation of positional cues results in the modification of Hox gene
coordinates themselves.
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Supplementary material
Supplementary material for this article is available at
http://dev.biologists.org/cgi/content/full/132/13/3093/DC1
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ACKNOWLEDGMENTS |
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