Department of Craniofacial Development, Dental Institute, Kings College London, Floor 28, Guys Hospital, London Bridge, London SE1 9RT, UK
* Author for correspondence (e-mail: paul.sharpe{at}kcl.ac.uk)
Accepted 2 June 2004
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SUMMARY |
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Key words: Oral epithelium, Ectoderm, Fate map, DiI, DiO, Chick
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Introduction |
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It has been established that the expression of transcription factors (and consequently the establishment of the proximodistal domains in the ectomesenchyme of the developing mandible) is controlled by the spatially restricted expression of signalling factors in the overlying oral epithelium. This suggests that the oral epithelium contains a crude proximodistal pre-pattern that is transferred and refined into overlapping proximodistal domains of homeobox genes in the ectomesenchyme. This proximodistal regionalisation of the oral epithelium is fundamental to patterning of the hard tissue of the jaws and, in heterodontic mammals, also of teeth.
Although the origins of the neural crest cells in the first pharyngeal arch
have been mapped (Couly et al.,
1996; Lumsden et al.,
1991
) (reviewed by Graham,
2001
), relatively little attention has been paid to the origins of
the surface epithelium of the mandibular primordium. Because this epithelium
appears to contain the first patterning information in the developing lower
jaw, it is important to understand how this early pattern is produced. One
possibility is that ectodermal cells in the mandibular primordium having a
proximal fate have a different developmental origin and history to the cells
that have a distal fate. In order to investigate the lineage origins of the
oral epithelium, DiI/DiO-lineage tracing was used to follow the fate of early
cranial surface ectoderm cells. Developmental stages after the head-process
stage were chosen for this study because previous work by Streit indicates
that at earlier stages otic, neural crest, epibranchial placode and epidermis
cell precursors were all intermingled
(Streit, 2002
). We thus chose
this stage as our starting point to help map the process through which
proximal and distal ectoderm territories become defined.
Avian embryos were chosen because of the ease with which lineage tracing
can be performed. Expression of epithelial signalling molecules and
mesenchymal transcription factors in the early developing first pharyngeal
arch is largely conserved between chick and many other vertebrates, including
mouse, and one might expect that the mechanism of proximodistal patterning of
the mandibular primordium is also similarly conserved
(Chen et al., 2000).
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Materials and methods |
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Ectoderm labelling with DiO crystals
DiO crystals were produced and added to the embryo surface ectoderm as
described by Clarke (Clarke, 1999). In addition to the x and
y co-ordinates, the position of the label was recorded by digital
photography.
Dissection and fixation
Embryos were dissected from the eggs and the extra-embryonic membranes
removed. The embryos were fixed at 4°C in 4% paraformaldehyde (PFA)
overnight and then transferred to 1% PFA for storage.
Microscopy and photography
Using epifluorescent microscopy, cells labelled with either CM-DiI or DiO
were identified. DiI-labelled cells were observed using a rhodamine, 590 nm
barrier filter (Leica), and DiO-labelled cells with a GFP2, 510 nm low-pass
barrier filter (Leica). Photographs of the embryos were taken under both
visible and epifluorescent light and the images merged using PhotoShop (Adobe,
USA).
Vibratome sectioning
Following whole-mount photography, embryos were embedded in 20% gelatin
diluted into PBS and the blocks submerged in 4% PFA for 48 hours. Vibratome
sections (40 µm thick) were cut and mounted under a glass coverslip in
Vectashield mounting solution (Vector Laboratories, UK).
In situ hybridisation
In situ hybridisation was performed on PFA-fixed embryos as described by
Mootoosamy and Dietrich (Mootoosamy and
Dietrich, 2002). Chick Fgf8 and Bmp4 cDNA probes
were kindly provided by Ivor Mason and Anthony Graham, respectively.
Isolation of coronal tissue explant containing the presumptive mandibular region
Eggs were incubated as described above, or until they had reached stage 9,
and the whole embryo dissected from the surrounding membranes in Dulbecco's
Modified Eagle's medium (Sigma) supplemented with 10% foetal calf serum
(Gibco-BRL). The stage 9 embryos were positioned with the ventral side facing
upwards. Using fine tungsten needles a coronal cut was made approximately
two-fifths of the distance between the anterior neuropore and the sub-germinal
fold. The most rostral segment containing the neuropore was discarded. The
remaining head tissue rostral to the sub-germinal fold was then isolated by a
second incision just above the sub-germinal fold. The caudal head and trunk
tissue was discarded. The remaining coronal head segment contained the
presumptive mandibular region as predicted from the fate map.
Isolation of ventral tissue explant
Coronal segments were isolated as described above and placed so that the
neural tube and foregut endoderm were visible. Using fine tungsten needles
incisions were made on the lateral edges cutting through the surface ectoderm,
mesoderm and foregut endoderm (e.g. Fig.
8A). At the midline, the ventral and dorsal foregut endoderm are
closely apposed, so at this point the ventral tissue fragments had to be
carefully teased away from the more dorsal tissue. The dorsal tissue fragment
containing the neural tube was discarded and the ventral tissue explant
cultured.
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Unilateral endoderm removal
Using fine tungsten needles a ventral-medial incision was made in the
isolated coronal head segment (isolated as described above). The ventral head
tissue was opened out and fine tungsten wire (0.1 mm; Goodfellow) was inserted
between the apposing ectoderm and endodermal tissues on the right side of the
head segment. It is notable that at stage 9, the neural crest cells have not
yet completed their migration, so between the ectoderm and the endoderm there
is a large amount of extracellular space. Therefore, using the tungsten wire,
it is possible to dissect and remove the endoderm tissue from the
ectoderm.
Culture of chick explants
Tissue explants were cultured under the conditions described by Tucker et
al. (Tucker et al., 1998a;
Tucker et al., 1998b
).
Briefly, explants were placed on nitrocellulose membrane filters (Millipore),
supported by stainless steel mesh (Goodfellow), in organ-welled dishes, and
partly submerged in MEM supplemented by 10% FBS. Explants were cultured at
37°C in a humidified incubator containing 5% CO2 for 2-3 days.
Following incubation, growth was stopped by adding ice cold 100% methanol and
fixing in 4% PFA, as described previously.
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Results |
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Out of 325 embryos labelled, 98 survived incubation, reaching stages of between 18 and 22. Embryos having craniofacial malformations or morphological differences between the labelled side and the unlabelled control side were discarded. The remaining embryos emitting fluorescence were vibratome sectioned to confirm that the label was indeed on the surface epithelium and not in the underlying mesenchymal cells. In total, 59 embryos containing epithelial DiI/DiO label were analysed further, and the final location of DiI/DiO following incubation recorded. Particular note was taken of the presence or absence of fluorescence in the maxilla and the location on the mandible. The proximal epithelium of the mandibular primordium was characterised as both the oral region, where Fgf8 (Fig. 1E,F) is expressed, and the part of the mandible away from the oral aspect. Regions more distal to this were characterised as distal epithelium (Fig. 1E,G). As fluorescence of DiI and DiO is lost following in situ hybridisation, the characterisation of whether the label was proximal or distal was predicted by comparison of the position of the label in the experimental embryo with a stage-matched embryo on which an Fgf8 in situ hybridisation had been performed.
Labelling from the dorsal aspect of stage 8-10 embryos did not result in any ectodermal fluorescence in the oral region at stages 18-22, except when the lateral edges were labelled. These data indicate that relative to the dorsal side of the embryo, only cells on the very lateral edge are able to give rise to the cells on the epithelium of the mandibular and maxillary primordia. The locations along the lateral edge of labels that gave rise to the ectoderm rostral to the maxillary primordia, maxilla, oral and aboral mandible were found to be distinct, even as early as stage 8 (Figs 2, 3). The relative distance along the vertical axis of the embryonic head, and the region where the mandibular primordium was labelled, was comparable between stages 8 to 10 (Fig. 2). When cells on the most dorsolateral edge were labelled, at a distance approximately one third of the distance between the anterior neuropore and the first somite at stage 9 (7 somites), fluorescence was observed in the oral maxillally primordium and in the most proximal region of the oral epithelium of the mandibular primordium (Fig. 3A-D). When the lateral edge was labelled from the dorsal aspect at the same stage but more caudally, approximately halfway between the anterior neuropore and the first somite, the aboral surface of the first branchial arch was fluorescent (Fig. 3E,F). Labels were also identified in the maxillary primordia of the first pharyngeal arch (Fig. 3G), and in more rostral regions (Fig. 3H). Thus, the epithelium of the different jaw primordial is demarcated early in the development of the head.
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When cells close to the ventral lateral edge at the level predicted to contribute to the primordia of the mandible and maxilla were labelled, they populated the same areas of the facial epithelium as those from the dorsal most lateral edge (Fig. 4A-C). This suggested that the same group of cells were being labelled in both experimental sets. Labelling closer to the ventral midline resulted in cells populating the distal oral epithelium. Where cells adjacent to the ventral midline were labelled, the most distal part of the mandibular primorium contained fluorescence (Fig. 4D-F).
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The close proximity of endoderm to the Fgf8-positive ectoderm
suggested that endoderm might have a role in regulating ectodermal
Fgf8 expression. This was tested by physically ablating the endoderm
from one side of the dissected tissue explants of stage 9 embryos, adjacent to
the Fgf8-positive ectoderm (Fig.
9A,D). Ablation was performed at stage 9, prior to the onset of
Fgf8 expression in the presumptive mandibular region. After 2.5 days
in culture, expression was not present in the ectoderm from the ablated side
but was present in the control side of the explants
(Fig. 9D,E). Dorsoventral
signalling from the endoderm is thus required for the early ectodermal
expression of Fgf8 that marks the precursors of the proximal oral
epithelium. This data supports the work of Couly et al.
(Couly et al., 2002), who
ablated whole stripes of endoderm in ovo at stage 8+ to 9. The area
that they categorised as stripe 2 corresponds to the endoderm underlying the
presumptive maxilla and mandible ectoderm. Following 5 days of incubation,
they observed underdevelopment of both the maxillary and mandibular primordia,
and absence of Meckel's cartilage on the operated side. Additionally, they
also observed partial loss of expression of the transcription factor
Pitx2 on the operated side. Interestingly, Withington et al.
illustrated that the endoderm was required for the expression of Fgf8
in the forebrain (Withington et al.,
2001
). Removal of definitive endoderm at stage 4+ to 5 resulted in
the loss of Fgf8 expression in the forebrain at stage 11.
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In order to determine whether the ventral-medial tissues of stage 9 embryos
have an intrinsic ability to express Bmp4 independently of planar
signals from the ventral-lateral tissues, ventral-medial and ventral-lateral
tissues, tissue explants of stage 9 embryos were dissected
(Fig. 8). These explants were
cultured for 2.5-3 days and assayed for Bmp4 expression. Both
ventral-lateral and medial-lateral cultured explants express Bmp4
(Fig. 8). The observation that
the ventral-medial explants express Bmp4 does indeed suggest that the
cells of stage 9 embryos are fated to express Bmp4 later in
development. However, the fact that the ventral-lateral tissues also express
Bmp4 indicates that the situation may be more complex. One
explanation for the observation that Bmp4 is expressed in both sets
of explants may lie with the dynamic expression of Bmp4 in the
developing chick head, and the fact that tissues in culture do not develop at
the same rate as those in vivo. Another possible reason might be because
Bmp4 is also expressed in the developing maxillary primordia
(Wall and Hogan, 1995) of the
developing first pharyngeal arch and our fate mapping indicates that, like the
proximal mandibular epitheium, the ectoderm of the maxillary primordia arises
from the lateral surface ectoderm of the early embryonic head. At stage 14,
when the distal mandibular ectoderm begins to express Bmp4 the
endoderm no longer underlies the ectoderm. Also by stage 14, migrated neural
crest cells occupy tissue underlying the ectoderm in the first pharyngeal
arch, hence creating a physical barrier to signalling molecules arising from
the endoderm. At stage 14, it is therefore unlikely that signals from the
endoderm are responsible for the highly localised and restricted expression of
Bmp4 in the distal ectoderm of the mandible primordium.
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Discussion |
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The work of Couly et al. implicates the foregut endoderm as a major source
of patterning signals (Couly et al.,
2002). They found that, in the early chick, the foregut endoderm
is able to pattern the non-Hox expressing cranial neural crest cells that
occupy the jaw. Their data indicates that, at a general level, the endoderm
appears to specify the identity and polarity. However, the nature of the
signals arising from the endoderm is at present unknown.
Previous work in our laboratory, and in numerous others, indicates that the
oral ectoderm plays an important role in the high resolution patterning of the
neural crest of the first pharyngeal arch. In order for the skeletal elements
of the jaw to be shaped, positioned and orientated correctly in
three-dimensional space, the mesenchyme of the mandible must be patterned
along three different axes. These axes can be described as rostrocaudal,
proximodistal and dorsoventral. The early patterning of the mesenchyme of the
mandibular primordium along these three axes is reflected in the specific
graded expression of numerous transcription factors. For example,
Lhx6 and Lhx7 are expressed exclusively in the rostral
mesenchyme, in contrast to Gsc, which is expressed specifically in
the caudal region (Tucker et al.,
1999).
Expression of Barx1 marks the proximal mesenchyme of the
mandibular primordium, whereas Msx1 is expressed in the distal
mesenchyme. The expression of these transcription factors is controlled by
signalling molecules originating in the oral ectoderm. The expression of
Fgf8 proximally and Bmp4 distally induces the expression of
Barx1 and Msx1, respectively
(Ferguson et al., 2000;
Tucker et al., 1998a
;
Tucker et al., 1998b
). We are
interested in how the skeletal structures of the jaw are patterned in the
proximodistal direction. Although it has been established that the
proximodistal ectomesenchyme is patterned as a result of spatially restricted
signals arising from the oral ectoderm, how the spatially restricted
expression domains in the oral ectoderm are established and maintained, and
how they interact with each other, is at present not fully understood.
Gene expression studies suggest that the proximodistal patterning of
orofacial epithelium is evident in the chick embryo from stage 14, when
distinct domains of Fgf8 and Bmp4 expression are first
visible (Shigetani et al.,
2000). Important questions are: when are these territories
specified and does this require the presence of neural crest-derived cells?
Shigetani et al. identified a domain of Fgf8 expression in the
ventral head ectoderm of stage 11 chick embryos in the presumptive
maxillo-mandibular region (Shigetani et
al., 2000
). As development proceeds, the Fgf8 expression
domain expands and corresponds to the developing maxillary and mandibular
prominences. DiI labelling of the stage 11 to 12+ chick Fgf8
expression domain indicated that it did demarcate the cells fated to occupy
the epithelium of the proximal oral mandibular primordium. The expression of
Bmp4 in the early developing chick embryo is however more dynamic.
Shigetani et al. (Shigetani et al.,
2000
) first observed expression of Bmp4 in the rostral
head ectoderm at stage 12. Weak expression was observed ventral to the
presumptive pharyngeal ectoderm. At stage 13, more distinct expression was
reported; this expression was ventral to, and had a slight overlap with, the
Fgf8 expression domain. Shigetani et al.
(Shigetani et al., 2000
) first
reported distinct expression of Bmp4 in the distal domain of the
pharyngeal arch at stage 14. It therefore seems that Bmp4 does not
demarcate the distal pharyngeal ectoderm until stage 14.
In order to understand the origin of the morphogenic signals that pattern
the oral ectoderm, we have fate mapped the cells that give rise to the
proximal and the distal domains of the oral ectoderm. Labelling of the
ectoderm between stages 8 to 10, predicted that the progenitor cells of the
mandibular primordium were located at a level between one-quarter and
two-fifths of the distance between the anterior neuropore and the first somite
along the anteroposterior axis. Couly and Le-Douarin
(Couly and Le-Douarin, 1990)
crudely segmented the surface ectoderm between the anterior neuropore and the
first somite of a stage 8 (3 somite) embryo into six ventrolateral segments of
equal width, and transplanted these segments between quail and chick.
Transplanting a tissue strip one-sixth and one-third of the distance between
the anterior neuropore and the first somite resulted in quail cells occupying
the ectoderm overlying the maxillary and mandibular primordia. The results we
present using DiI/DiO labelling are consistent with data of Couly and
Le-Douarin (Couly and Le-Douarin,
1990
). However, our more precise mapping reveals that, from at
least stage 8, the cells fated to occupy the proximal and the distal oral
ectoderm occupy different spatial locations in the developing embryo. The fate
map thus shows that the cells that go on to express Fgf8 in the
proximal oral epithelium of stage 18 to 22 chicks are located on the
ventral-lateral head ectoderm as early as stage 8. Cells in the distal oral
mandibular primordium (which at stage 14 start to express Bmp4)
occupy a more medial position in the early chick embryo. This data indicates
that the cells occupying the proximal and the distal mandibular primordia
occupy different locations in the early embryo and, consequently, are likely
to have a different developmental history.
As the cells are located at different positions in the head, it is possible
that they are exposed during their developmental history to different
morphogens, or perhaps different concentrations of morphogenic factors. These
factors may be planar or may arise from the underlying mesenchyme or endoderm.
Prior to neural crest migration and the cranial neural crest cells reaching
the maxillo-mandibular region, the ectoderm of the mandible is in close
proximity to the foregut endoderm. Couly et al. implicated the foregut
endoderm as a source of morphogenic signals responsible, at least in part, for
patterning the skeletal elements of the jaw
(Couly et al., 2002). Removal
of the endoderm that is in close proximity to the Fgf8-positive head
ectoderm in stage 9 embryos resulted in a loss of expression of Fgf8.
When the ventral head tissue was dissected from the dorsal tissue at stage 9
(Fig. 8), and earlier (data not
shown), and cultured in vitro, Fgf8 expression was still observed.
This indicates that absent or aberrant neural crest migration is not
responsible for the failure of ectoderm to express Fgf8 in the
absence of endoderm. It also suggests that, in addition to its role in
patterning facial mesenchyme, the endoderm has an earlier role in patterning
the orofacial ectoderm.
Although the ventral-lateral head ectoderm and the more medial head ectoderm are fated to occupy different positions on the oral ectoderm, the point at which they are specified to follow either the `proximal' or `distal' developmental route is unclear. Fgf8 is not expressed in the ventral head ectoderm until stage 11, our DiI labelling of cells at these stages suggests that these are indeed the same cells that later go on occupy the proximal epithelium at stages 18 to 22. Bmp4 expression is much more dynamic, and it is not until stage 14 that it is expressed specifically in the distal epithelium. When and how during development the proximal and distal ectoderm is induced and programmed to express Fgf8 and Bmp4, and when the proximal or distal fate is specified, is currently under investigation. However, we speculate that the proximal and the distal ectoderm are both specified and committed to their respective fates independently and at different times during embryogenesis.
Candidate molecules within the head ectoderm that may play a role in the
control of Fgf8 and Bmp4 expression include Pitx2
(Amand et al., 2000).
Pitx2 is a bicoid transcription factor that is expressed in the early
developing embryo and has overlapping expression domains with Fgf8.
In the chick, Pitx2 has been shown to be expressed in the presumptive
maxillomandible region of stage 11 embryos
(Amand et al., 1998
). The data
of Lu et al. (Lu et al., 1999
)
showed that mice null for Pitx2 have defective development of the
maxillo-mandible facial prominences. Lu et al. suggested that the expression
of Fgf8 is absent in these mutants
(Lu et al., 1999
); however,
Lin et al. reported that, in mice null for Pitx2, Fgf8 was still
expressed in the facial region, albeit at a reduced level
(Lin et al., 1999
). Lu et al.
(Lu et al., 1999
) reported
that the expression of Bmp4 in the Pitx2 null mutants
expanded into the whole proximodistal ectoderm mandibular primordium. This
mandibular phenotype is comparable to that reported by Stottmann et al.
(Stottmann et al., 2001
) in
Noggin/Chordin null mutant mice. Whether (or how) Pitx2 expression
affects Noggin expression is not known. Whether Pitx2 is responsible
for initiating the expression of Fgf8 in the developing ventral
ectoderm of the embryonic head, or whether it is only responsible for its
maintenance, is at present unclear from the literature.
In summary, we have identified cells in the chick embryo that are fated to occupy the proximal and distal oral ectoderm of the mandibular primordium. We have found that cells fated to occupy the proximal (Fgf8-expressing) domain and distal (Bmp4-expressing) domains of stage 18 to 20 chick mandible epithelium occupy different spatial locations as early as stage 8 in ventral head ectoderm, prior to the formation of neural crest. In addition, the cells on the ventral head ectoderm that express Fgf8 at stage 11 to 12 are the same cells that are fated to occupy the proximal oral mandibular primordium and that express Fgf8 at stage 18 to 22. The co-ordination and control of orofacial morphogenesis is thus a process that begins early in embryogenesis with the demarcation of boundaries in the cranial ectoderm that prefigure the proximodistal organisation of oral epithelium.
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ACKNOWLEDGMENTS |
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