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First published online June 6, 2008
doi: 10.1242/10.1242/dev.020123
Research Report |
1 Evolution des Régulations Endocriniennes, CNRS UMR 5166, Muséum
National d'Histoire Naturelle, Paris, France.
2 Service de Chirurgie Plastique, Maxillofaciale et Stomatologie, Hôpital
Necker-Enfants Malades, 149, rue de Sèvres, 75015 Paris, France.
3 Biologie du Développement, CNRS UMR 7622, Université Pierre et
Marie Curie, Paris, France.
Authors for correspondence (e-mails:
glevi{at}mnhn.fr;
gerard.couly{at}nck.ap-hopparis.fr)
Accepted 29 April 2008
SUMMARY
Morphogenesis of the facial skeleton depends on inductive interactions between cephalic neural crest cells and cephalic epithelia, including the foregut endoderm. We show that Shh expression in the most rostral zone of the endoderm, endoderm zone I (EZ-I), is necessary to induce the formation of the ventral component of the avian nasal capsule: the mesethmoid cartilage. Surgical removal of EZ-I specifically prevented mesethmoid formation, whereas grafting a supernumerary EZ-I resulted in an ectopic mesethmoid. EZ-I ablation was rescued by Shh-loaded beads, whereas inhibition of Shh signalling suppressed mesethmoid formation. This interaction between the endoderm and cephalic neural crest cells was reproduced in vitro, as evidenced by Gli1 induction. Our work bolsters the hypothesis that early endodermal regionalisation provides the blueprint for facial morphogenesis and that its disruption might cause foetal craniofacial defects, including those of the nasal region.
Key words: Sonic hedgehog, Cephalic neural crest cells, Endoderm, Foregut, Mesethmoid, Nasal capsule, Chick
INTRODUCTION
The nasal capsule is dorsoventrally divided into two parts: the upper part, the ectethmoid, serves olfaction and is composed of the lamina cribosa, the crista galli apophysis and the conchae. The lower part, the mesethmoid, is a thick cartilage bar extending from the corpus sphenoidalis to the rostral extremity of the nose (Fig. 1A-B'). In the avian embryo, the mesethmoid constitutes the cartilage primordium of the upper beak.
Lineage experiments have shown that Hox-negative cephalic neural crest
cells (CNCCs) emigrating from the prosencephalic and the anterior
mesencephalic neural folds give rise to the nasal capsule and to first
pharyngeal arch (PA) structures (Couly et
al., 1993
; Creuzet et al.,
2002; Kontges and Lumsden,
1996; Noden, 1992;
Trainor and Tam, 1995). By
contrast, Hox-positive NCCs, which are only found posteriorly to rhombomere 2,
do not contribute to the facial skeleton, but generate more-posterior
structures of the embryo (Couly et al.,
1996; Kontges and Lumsden,
1996; Santagati and Rijli,
2003). Premigratory, Hox-negative CNCCs behave as an equivalence
group and lack the topographic information needed to give rise to the
different structures of the craniofacial skeleton
(Couly et al., 2002). We have
shown by surgical deletion and grafting of different parts of the foregut
endoderm that this epithelium harbours the instructive signals
(Couly et al., 2002;
Noden, 1992;
Ruhin et al., 2003), although
their molecular nature remains to be determined. Among candidate cues, sonic
hedgehog (Shh) is expressed in the most anterior part of the
endoderm, endoderm zone I (EZ-I), of the early chick embryo
(Brito et al., 2006). Later,
incoming CNCCs express the Shh receptor patched 1, indicating a potentially
active Shh signalling (Jeong et al.,
2004). The importance of Shh signalling in the control of
different aspects of craniofacial development has been demonstrated in several
models including zebrafish (Wada et al.,
2005), mouse (Chiang et al.,
1996; Jeong et al.,
2004) and chicken (Brito et
al., 2006; Cordero et al.,
2004; Helms et al.,
1997; Hu et al.,
2003). Furthermore, human syndromes with nasal malformations, such
as foetal alcohol syndrome, Smith-Lemli-Opitz syndrome and holoprosencephaly,
have been associated with defective SHH signalling
(Herman, 2003;
Traiffort et al., 2004;
Yamada et al., 2005).
MATERIALS AND METHODS
Avian embryos
Fertilised eggs were obtained from Morizeau Farms, France (chicken,
Gallus gallus) or Cailles de Chanteloup Farms, France (quail,
Coturnix coturnix japonica) and incubated at 38°C in a humidified
atmosphere for approximately 32 hours to reach the 5-somite stage HH8+
(Hamburger and Hamilton, 1992;
Teillet et al., 1998). Embryos
were collected and dissected at room temperature in phosphate-buffered saline
(PBS).
Embryo processing
Immunoperoxidase detection was performed as previously described
(Couly et al., 2002). Quail
nuclei were detected with the quail-specific monoclonal antibody QCPN at 1/500
(obtained from the Developmental Studies Hybridoma Bank developed under the
auspices of the NICHD and maintained by The University of Iowa, Department of
Biological Sciences, Iowa City, IA 52242). Chick and quail Gli1 proteins were
detected using rabbit polyclonal antibody #2553S (Cell Signaling Technologies)
at 1/200. Shh transcripts were detected by in situ hybridisation as
previously described (Couly et al.,
2002). Whole-mount skeletons were visualised according to standard
staining protocols using Alcian Blue for cartilage and Alizarin Red for bone
(Couly et al., 2002).
Ablation of EZ-I
Experiments were carried out in ovo on windowed chick embryos at the
5-somite stage HH8+ (Couly et al.,
2002). Two bilateral excisions were first performed on the
superficial ectoderm on each side of the neural tube at the level of the
prosencephalon and down to the mesencephalon (see Fig. S1 in the supplementary
material). A very fine curved tungsten microknife was then passed under the
neural tube and the notochord, resulting in their separation from the dorsal
foregut endoderm. A transversal incision was then performed on the neural
plate at the level of the posterior mesencephalon. The neural epithelium was
reclined rostrally in order to gain access to the endoderm. The ventral
endoderm was separated from the ventral ectoderm by passing a very fine curved
tungsten microknife between the two tissues. The rostral-most attachment
between the ventral endoderm and the anterior neural fold was then cut. At
this point, the ventrolateral endoderm was free of any attachment and we could
then easily remove the EZ-I by performing a transversal incision at a distance
of 
150 µm from its rostral end, and 100 µm in front of the
anterior intestinal portal vein. At this stage, the caudal domain is EZ-II
(Couly et al., 2002). The
neural tube and the ectoderm were then delicately placed back in their initial
position, where they rapidly reconnected with the rest of the embryonic
tissues, resuming their development with no obvious defects. In a series of
experiments, before closing the embryo, we placed a heparin acrylic bead
(Sigma) in the vacant region where the EZ-I had been ablated. Embryos were
reincubated until stage HH35 for morphological and chondrocranial
analysis.
|
Effects of Shh- or cyclopamine-loaded beads
Experiments were carried out in ovo on windowed chick embryos at the
5-somite stage (Couly et al.,
2002). For rescue experiments using Shh, heparin beads (120 µm
diameter; Sigma, St Louis, MO) were soaked in 100 µg/ml mouse recombinant
Shh (R&D systems, Minneapolis, MN) in PBS for 1 hour at 37°C, then
rinsed three times in PBS immediately prior to use. Beads soaked in 0.1% BSA
were used as control. EZ-I was ablated as previously described and then one
bead was placed in the vacated territory. For experiments with cyclopamine,
heparin beads were soaked in crystalline 11-deoxyjervine (Toronto Research
Chemicals, Toronto, Canada) at 4 mg/ml in 95% ethanol, and then rinsed three
times in PBS prior to use (Watkins et al.,
2003). Control beads were soaked in PBS.
Culture and analysis of endoderm and CNCC explants
Microdissected tissue fragments from transverse domains of the
ventrolateral endoderm or bilateral neural plate apical ridges were collected
as illustrated in Fig. 4A
(Couly et al., 2002;
Ruhin et al., 2003).
Endodermal stripes and neural crest fragments were washed in PBS, then either
deposited onto 0.4 µm porosity Millipore nylon inserts
(Gitton et al., 1999) or onto
glass Lab-Tek multichambered slides (Nunc) for up to 48 hours and cultured in
Dulbecco's Modified Eagle Medium (Gibco, France). This defined medium was
supplemented with a 1:1 mix of serum replacement medium (Sigma) and B27
solution (Gibco), a 1:1 mix of penicillin and streptomycin antibiotic mix (25
µg/ml and 25 U/ml) and L-glutamine (2 mM, Gibco) as previously
described (Dahmane et al.,
2001). Pharmacological treatments included 20 µM cyclopamine
(R&D Systems) or 10 µM Shh [recombinant mouse N-terminal fragment
(Shh-N), R&D Systems] diluted in the culture medium. Significant cell
emigration was observed around neural crest explants as early as 12 hours
after incubation.
At the end of the culture period, the explants and surrounding cells were gently washed in culture medium, scraped and detached from the support and collected for total RNA extraction using the RNeasy Microkit (Qiagen). To obtain equivalent amounts of extracted material, equivalent numbers of tissue fragments were used, i.e. two EZ-1 or two bilateral CNCC fragments were equated with each co-culture of EZ-1 and CNCCs. For random hexamer-primed reverse transcription into total cDNA, we used the RT-PCR First-Strand Synthesis System (Invitrogen) including DNaseI treatment. Negative controls that omitted the Superscript II reverse transcriptase demonstrated that all samples were free of contaminant nucleic material (data not shown). Total cDNAs were analysed by PCR in the linear amplification range (30 cycles). Expression of chicken Gapdh, Shh and Gli1 was monitored by PCR; primers and conditions are available upon request.
RESULTS AND DISCUSSION
To determine the function of EZ-I in the control of craniofacial development, we first ablated this endodermal territory in ovo from 5-somite chick embryos, well before CNCC migration (Fig. 1C; see Fig. S1 in the supplementary material) and analysed their skeletal morphology at Hamburger Hamilton stage 35 (HH35). In all surviving embryos (8/19), the mesethmoid cartilage was absent or severely reduced, whereas the ectethmoid and the infraorbital septum were always present and of relatively normal size and shape (Fig. 1D,D'). The adjacent ectoderm, neural tube and first arch CNCC derivatives developed normally.
Next we transplanted a supplementary EZ-I from 5-somite quail embryos into
the presumptive nasal capsule territory of stage-matched chick embryos and
analysed skeletal morphology at HH35. All survivors (12/21) displayed one
ectopic, supernumerary mesthemoid-like cartilage
(Fig. 2A,B,B') next to
the normal and complete nasal capsule. Heterotopic quail EZ-I grafts,
implanted within the 5-somite chick presumptive first PA territory, induced a
supernumerary mesthemoid-like element in 10/12 survivors
(Fig. 2C,D). Dermatocranial
elements [putatively premaxillary bones
(Couly et al., 1993)] formed
in close proximity to the supernumerary cartilage. All other first and second
PA derivatives developed normally. Both homotopic and heterotopic grafts
suggest that EZ-I is necessary and sufficient to induce the differentiation of
any Hox-negative CNCC contingent into a mesethmoid cartilage. Ectopic
cartilage elements consistently failed to develop when we grafted EZ-I into
the Hox-positive neural crest domain (data not shown).
|
|
) could be
responsible for its capacity to induce mesethmoid formation. First, we doubly
transplanted EZ-I and CNCCs from 5-somite quail into stage-matched chicken
embryos. In all cases, the grafted EZ-I was strongly Shh-positive and
was in close contact with grafted post-migratory CNCCs (Fig.
3A-C). We then transplanted
EZ-I into the presumptive first PA close to the ocular region and observed a
strong ectopic induction of Gli1, a Shh target
(Dahmane et al., 2001) not
normally expressed in this area (see Fig. S2 in the supplementary material).
To determine whether Shh expression from EZ-I directly contributed to
mesethmoid induction, we ablated EZ-I from 5-somite embryos and implanted a
Shh-loaded bead in the vacant territory
(Fig. 3D). In all surviving
embryos (18/36), the nasal capsule presented a mesethmoid-like cartilage
correctly located under a normal ectethmoid
(Fig. 3E,E'). Control
BSA-loaded beads did not rescue the lack of mesethmoid resulting from EZ-I
ablation (n=6).
|
To address whether direct CNCC-EZ-I interaction could trigger Shh-Gli1 signalling, we examined organotypic cultures of endoderm and neural crest fragments from 5-somite embryos (Fig. 4A). We cultured the explants for 24 hours either alone or in combination. RT-PCR analysis of EZ-I explants alone indicated a weak constitutive Shh expression accompanied by a barely visible Gli1 signal. Conversely, neither Shh nor Gli1 transcription could be seen in CNCC explants. Co-cultures of EZ-I and CNCC fragments displayed substantially higher levels of Gli1 transcripts, as compared with either component alone. Shh levels were also increased. Cyclopamine inhibition of Shh-Gli1 transduction in the co-cultures prevented Gli1 expression and reduced Shh levels (Fig. 4A). Furthermore, co-cultures of CNCC explants and endoderm zone II (EZ-II) failed to display Gli1 expression, even after 48 hours in vitro (data not shown).
Consistent with the observation that endoderm-derived Shh activates Gli1 in CNCCs, recombinant Shh-N protein induced Gli1 in cultures of CNCCs alone, thereby reproducing the endoderm inductive effect. By contrast, exposure to either Shh-N or cyclopamine repressed Shh expression in cultures of endoderm explants.
Collectively, our in ovo and ex ovo data suggest a reciprocal, cyclopamine-sensitive interaction between EZ-I and uncommitted CNCCs. Shh expression increases in the rostral-most endoderm following contact with post-migratory CNCCs (Fig. 4B). Shh, in turn, strongly induces Gli1 transcription in CNCCs. This inductive process leads to chondrogenesis, resulting in the formation of the mesethmoid cartilage (Fig. 4C), and later to the formation of the corresponding dermatocranial elements.
Our previous results suggested a very precise topographical engraving of
endodermal information as the orientation of the endodermal grafts was
precisely reflected in the shape and orientation of CNCC-derived ectopic
cartilages (Couly et al.,
2002).
Although the nature of these molecular clues is not yet elucidated,
candidates include Bmp4, Fgf8, Shh, endothelin 1, noggin and retinoic acid
(Foppiano et al., 2007;
Hu et al., 2003;
Lee et al., 2001;
Song et al., 2004;
Vieux-Rochas et al., 2007).
The importance of Shh signalling for craniofacial morphogenesis
(Brito et al., 2006;
Haworth et al., 2007) and CNCC
survival (e.g. Ahlgren and Bronner-Fraser,
1999; Brito et al.,
2006; Charrier et al.,
2001; Cordero et al.,
2004) has been reported previously, but the topological and
chronological significance of this pathway remains to be determined. In
particular, it has been shown that the maintenance of a boundary between the
territories of expression of Fgf8 and Shh in the frontonasal
process depends on reciprocal inhibitory interactions
(Abzhanov et al., 2007;
Abzhanov and Tabin, 2004;
Haworth et al., 2007).
Our observations imply that endoderm-derived Shh signalling, which takes
place already at the 5-somite stage, predates the ectodermal Shh contribution
to craniofacial patterning (Hu and Helms,
2001; Hu et al.,
2003). Globally, these results indicate that whereas early
mesethmoid differentiation requires EZ-I Shh expression, ectodermal
expression of Fgf8, Shh and Bmp4 controls the size and shape of the beak at
later stages of development (Cordero et
al., 2004; Hu et al.,
2003; Wu et al.,
2004). Shh is both a long-range diffusible morphogen and a
short-range contact-dependent factor
(Chuang and McMahon, 1999;
Johnson and Tabin, 1995).
Here, ablation of EZ-I, a topographically restricted source of Shh in the
embryo, leads to a morphological lesion limited to the mesethmoid. This
implies that, at least in this context, the action of Shh takes place in a
localised paracrine, possibly contact-mediated, fashion. The human mesethmoid
cartilage gives rise to the nasal septum and the vomer. It thus contributes to
determining the proximodistal size of the nose and the position of the
premaxillary bone. Our results could help to clarify the origin of a number of
malformations of the nasofrontal bud
(Couly, 1981) that are
characterised by abnormal mesethmoid development, with normal ectethmoid.
These pathologies include, for example, cases of hypo- and
hyper-septoethmoidism such as a flat nose, short nose or very pronounced nose
and a median nasal cleft without cerebral anomalies. Thus, although as yet we
cannot answer Cyrano de Bergerac's question "De quoi sert cette
oblongue capsule?" (What use this oblong capsule?), we may begin to
understand where this oblong capsule comes from.
Supplementary material
Supplementary material for this article is available at
http://dev.biologists.org/cgi/content/full/135/13/2221/DC1
ACKNOWLEDGMENTS
We gratefully acknowledge the helpful comments of Prof. Nicole Le Douarin, Prof. Barbara Demeneix and Dr Anne Grappin-Botton, and the logistical help of Dr Marie-Aimée Teillet. We thank Sophie Gourmet and Michel Fromaget for illustrations. This research was partially supported by the EU Consortium CRESCENDO (LSHM-CT-2005-018652) and the ANR project `GENDACTYL'.
Footnotes
* These authors contributed equally to this work. 
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