Department of Orthopaedic Surgery, 533 Parnassus Avenue, Suite U-453, University of California at San Francisco, San Francisco, CA 94143, USA
Author for correspondence (e-mail:
helms{at}itsa.ucsf.edu)
Accepted 14 January 2002
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SUMMARY |
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Key words: Craniofacial development, Patterning, Fgf, Shh, Neuroectoderm, Facial ectoderm, Neural crest, Frontonasal process, FNP, Branchial arch, Pharyngeal arch, Quail, Chick
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INTRODUCTION |
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There is an enormous literature indicating that the cranial neural crest,
which gives rise to the connective tissues of the face, carries out
cell-autonomous programs of differentiation. The rostrocaudal level of origin
(Noden, 1983;
Serbedzija et al., 1991
), the
expression of a `Hox code' (Hunt et al.,
1991b
; Hunt et al.,
1991c
) and the timing of emigration from the neural tube (e.g.
Artinger and Bronner-Fraser,
1992
; Bronner-Fraser and
Fraser, 1989
; Richardson and
Sieber-Blum, 1993
) are thought to impart a `pre-pattern' to neural
crest populations. These data support the conclusion that craniofacial
patterning is controlled by neural crest-derived mesenchyme (reviewed by
Dorsky et al., 2000
).
However, abundant data underscore the significance of environmental signals
in determining cell fate. The transplantation
(Baker et al., 1997;
Couly et al., 1998
;
Hunt et al., 1998
;
Schneider, 1999
) or ablation
(Raible and Eisen, 1996
) of
neural crest, the transplantation or ablation of local signaling centers
(Couly et al., 2002
), the
alteration of gene expression patterns by electroporation
(Creuzet et al., 2002
;
Grammatopoulos et al., 2000
),
in vitro co-culture experiments (Tyler and
Hall, 1977
) and experiments in which the addition of signaling
molecules transform cell identity (Lee et
al., 2001
) all indicate that neural crest cells retain a
considerable degree of plasticity. These data support the conclusion that
local environmental signals regulate craniofacial patterning by eliciting a
range of responses from an uncommitted population of neural crest.
We find the balance between neural crest pre-determination and plasticity
particularly compelling, and have pursued this issue in the context of
craniofacial morphogenesis. Our investigation focuses on the mechanisms that
regulate patterning and growth of the frontonasal process (FNP), which gives
rise to the mid and upper face, and (in birds) contributes to the upper beak.
Bird beaks exhibit an astonishingly variable morphology, ranging from that of
the Snail-Eating Coua to the Roseate Spoonbill and variations in beak shape
have been closely associated with adaptive radiation into new niches
(Darwin, 1859). Both aspects
make the question of how the beak attains its pattern a particularly enticing
problem to address. Our first postulation was that changes in beak morphology
could result from subtle alterations in epithelialmesenchymal interactions in
the FNP. Thus, we began our studies by examining the extent to which
ectodermal signals controlled patterning and growth of the FNP.
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MATERIALS AND METHODS |
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In situ hybridization
In situ hybridization was performed on whole avian embryos and paraffin
wax-embedded sections as described
(Albrecht et al., 1997).
Subclones of Shh, Ptc1, Gli1, Islet1, Lfng, Rfng, Fgf8, Fgf10, Barx1,
FgfR1-3, AP2, Bmp2, Bmp4, Bmp5, Bmp6, Bmp7, BmpR1a, BmpR2b, Noggin, Gremlin,
Follistatin, DAN, Wnt4, Wnt6, Wnt7a, Wnt7b, Wnt13, Wnt14, ß-catenin,
Tbx2, Tbx3, Dlx1, Engrailed1, Engrailed2, Frzb1, LEF, Notch, Delta and
Serrate were linearized to transcribe either 35S-labeled
or digoxygenin-labeled antisense riboprobes. The expression patterns of all of
these genes were examined at multiple stages during craniofacial development;
a subset of expression patterns is shown here. For 35S-labeled
riboprobes, the hybridization signal was pseudo-colored using Adobe Photoshop,
then superimposed onto an image of the tissue stained with Hoechst nuclear
stain (Sigma). Whole-mount in situ hybridization was performed as described
(Albrecht et al., 1997
).
Graft preparation and transplantation
Tissue grafts consisting of FNP ectoderm and mesenchyme were harvested from
stage 20 (Hamburger and Hamilton,
1951) quail embryos using sharpened tungsten needles (illustrated
in Fig. 2A). The FNP tissues
were placed in DMEM digested with Dispase (2.4 units/ml, on ice for 20
minutes) to facilitate separation of ectoderm from mesenchyme, then washed in
DMEM containing 1% BSA to stop the digestion. FNP ectoderm grafts, measuring
0.5-0.8 mm in height by 1.0-1.2 mm in width, and free of adherent mesenchyme,
were transferred into DMEM containing Neutral Red (23°C, 2 minutes), which
was added to facilitate visualization of the graft when transferred to the
host.
|
Immunohistochemistry
To detect quail cells, chimeric embryos were removed 12 and 24 hours, and 7
days after graft transplantation, fixed in Serra's, paraffin wax embedded, and
cut into 10 µm sagittal sections. Immunodetection of quail cells used QCPN,
the quail-specific monoclonal antibody (Developmental Studies Hybridoma Bank),
followed by incubation with a second antibody conjugated to Horseradish
peroxidase (HRP). Diaminobenzidine (DAB, Sigma) was used to detect HRP.
Sections were counterstained with Fast Green FCF (Fisher) and imaged using
brightfield optics.
Bead implantations
Heparin sulfate beads (200-250 µm diameter; BioRad) were soaked in a
solution containing Fgf2 protein (400 µg/ml; R & D Systems), at
37°C for 1 hour. Affi-Gel Blue beads (50-100 mesh, 200-250 µm diameter;
BioRad) were soaked in recombinant Shh-N protein (400 µg/ml in PBS with
0.1% bovine serum albumin; Ontogeny) at 37°C for 1 hour. Fgf2 beads, Shh-N
beads, or a combination of both beads were implanted into the dorsal FNP of
stage 25 embryos, underneath the host ectoderm. When a bead and a graft were
combined, the graft was positioned, stabilized with glass pins in three
corners, and then the bead was placed beneath the edge of the graft. The
fourth corner of the graft was secured with a glass pin as described. Seven
days later, embryos were examined for morphological alterations by gross
examination and histology.
Histology
Embryos were sacrificed at stage 36; their heads were fixed in 4% PFA
overnight at 4°C, dehydrated and embedded in paraffin wax. Heads were cut
into 10 µm sagittal sections, which were stained with Milligan's Trichrome
(Presnell and Schreibman,
1997).
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RESULTS |
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Transplantation of the FEZ alters dorsoventral patterning of the
FNP
We suspected that the FEZ controlled aspects of dorsoventral patterning in
the FNP, and developed a transplantation strategy to test this possibility. In
the first set of experiments, we grafted the FEZ from a quail embryo onto the
dorsal FNP of a stage 25 chick host (Fig.
2A-C). We performed these heterochronic transplants because a
stage 25 FNP is sufficiently large to accommodate a FEZ graft without
disrupting or interfering with ectoderm at the tip of the FNP. In our first
experiment, the orientation of the FEZ graft was maintained in the host
(Fig. 2B,C). We collected
chimeric embryos and unoperated, stage-matched controls for the first analyses
12 hours after transplantation. We used in situ hybridization to demonstrate
that the graft was appropriately positioned in the host, and continued to
express Fgf8 and Shh in its ectopic position (n=7,
Fig. 2D,E). We used QCPN
immunostaining to confirm that the graft was composed entirely of ectodermal
cells from the quail donor, with no adherent mesenchyme (n=7,
Fig. 2F).
Within 12 hours the FEZ graft induced cell proliferation and re-specified gene expression patterns in the underlying dorsal FNP mesenchyme. By 24 hours, these altered expression patterns were even more pronounced, and the first morphological evidence of an ectopic outgrowth was observed (n=15, Fig. 3). The changes in gene expression were consistent with the orientation of the graft; for example, Shh is normally restricted to ventral FNP ectoderm (Fig. 3A,D); when the FEZ was positioned in its original dorsoventral orientation (i.e., no rotation), a Shh-off/Shh-on/Shh-off/Shh-on pattern (from dorsal to ventral) was created in the chimeric ectoderm (n=10, Fig. 3B,E). Ectopic Ptc1 and Gli1 in the mesenchyme reflected the location of Shh in the ectoderm being induced beneath the Shh-positive regions and downregulated beneath the Shh-negative regions (Fig. 3H,K). We also analyzed chimeric and control embryos for Fgf8 expression. Although Fgf8 continued to be expressed in the optic recess (Fig. 3D-F), it was downregulated in the host FNP ectoderm and the FEZ graft by this stage. Nonetheless, downstream targets of Fgf signaling, including Msx1 and AP2, were upregulated under the previously Fgf8-positive dorsal part of the FEZ graft and downregulated under the Fgf8-negative ventral region of the FEZ (Fig. 4M,N,P,Q). Other genes, such as Lfng and most of the Bmp genes, were upregulated in FNP mesenchyme underneath the graft (Fig. 3S,T, and data not shown). When the graft was rotated 180° (Fig. 3C), we found the predicted reversal in the Shh pattern (e.g. Shh-off/Shh-on/Shh-off/Shh-on; Fig. 3F). Correspondingly, Ptc1 and Gli1 were upregulated in the mesenchyme under the ventral Shh domains (Fig. 3I,L) while dorsal genes such as Msx1 and Lfng were upregulated under dorsal regions of the FEZ graft and repressed under ventral regions (Fig. 3O,U). Neither Msx1 nor Lfng was expressed in the dorsal-most mesenchyme (Fig. 3O,U, arrowheads). The ability to re-specify gene expression in FNP mesenchyme was not shared by other ectodermal grafts, including stage 20 dorsal facial ectoderm (n=6) and stage 20 flank ectoderm (n=6).
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In contrast to a stage 25 FNP ectoderm graft, a FEZ graft dramatically altered facial pattern. In most cases (36/38), an enormous outgrowth was observed at the site of graft placement (Fig. 4H,K,N). We used the spatial relationships among the egg tooth, the premaxillary bone, and the prenasal process to define the dorsoventral axis of the structures induced by the FEZ. By these criteria, two ectopic upper beaks formed (Fig. 4H,I). These ectopic structures were mirror-image (e.g. dorsal-ventral/ventral-dorsal) duplications of one another; the autochthonous beak maintained its normal dorsoventral polarity (Fig. 4I). We annotated this pattern as DVVD/DV to reflect the polarity of the structures induced by the quail FEZ (in italics) and the autochthonous upper beak. The assignment of a DVVD pattern to the ectopic structures was further supported by molecular analyses performed 12 and 24 hours after grafting, which showed an Msx1/Shh/Msx1/Shh expression pattern in the FNP ectoderm (n=10; Fig. 3 and data not shown). Thus, the FEZ induced the formation of two new dorsoventral boundaries within the FNP, and the outgrowth of two ectopic upper beak structures, whose own dorsoventral polarity was determined by the graft.
Based on these data, we hypothesized that juxtaposing dorsal and ventral ectodermal domains would be sufficient to stimulate the outgrowth of beak structures. We tested this hypothesis by rotating the FEZ 180° prior to grafting, which positioned the ventral (Shh-positive) domain of the graft adjacent to the dorsal (Fgf8/Msx1-positive) domain of the host, and the dorsal domain of the graft adjacent to the ventral domain of the host (Fig. 4J). As predicted, the ensuing molecular pattern in the ectoderm was Msx1-Shh-Msx1-Shh (n=10; Fig. 3). Only one ectopic outgrowth was produced, which was a mirror-image duplication of the autochthonous beak (VD/DV; 7/7 cases, Fig. 4K,L). We did not detect the predicted third upper beak (Fig. 4J, question mark), presumably because of the failure to reprogram the dorsalmost mesenchyme (see Fig. 3O,U, arrows).
To explore further if juxtaposing dorsal and ventral domains was sufficient to induce outgrowth, we transplanted stage 20 ventral ectoderm to the dorsal surface of a stage 25 host FNP. By doing so, we theoretically created two new sites where dorsal and ventral tissues were apposed, and where outgrowth should ensue if our initial hypothesis was correct. We confirmed that the grafts comprised only ventral ectoderm (n=12, in situ hybridization data not shown), and examined chimeric embryos for morphological and histological alterations 7 days later. Ventral grafts were unable to induce FNP alterations analogous to those caused by the FEZ graft (n=14; data not shown). Taken together, these data show that FNP outgrowth does not necessarily result from the juxtaposition of dorsal and ventral FNP ectoderm. Instead, our data indicate that FNP outgrowth requires other signals unique to the FEZ domain, or unique to the mesenchyme underlying the FEZ.
The FEZ can override an existing FNP pattern
We explored the extent to which a FEZ graft could alter the endogenous FNP
pattern. First, we confirmed that removing stage 25 facial ectoderm truncated
the growth of the upper beak at the level of the nasal capsule (n=10,
data not shown) (see Hu and Helms,
1999). Next, we replaced FNP ectoderm with a FEZ graft, which had
been rotated 180° prior to transplantation. This rotation resulted in the
juxtaposition of ventral FEZ with dorsal host ectoderm and dorsal FEZ with
ventral host ectoderm (Fig.
4M). By rotating the FEZ, we were able to ascertain the extent to
which neural crest-derived mesenchyme was plastic versus pre-specified, with
regards to dorsoventral pattern. Two beaks were evident as a result of the
grafting (Fig. 4N,O). The first
beak, in the ectopic location, had a DV pattern. The second beak, in the
autochthonous location, lacked a (dorsal) premaxillary bone; in addition, the
egg tooth, which is a dorsal specialization, was now located at the apex of
the beak. Furthermore, the prenasal process was symmetrically shaped rather
than exhibiting a typically convex dorsal surface and concave ventral surface.
Thus, we ascribed a VDV pattern to the second beak
(Fig. 4N,O). These results
demonstrated that the FEZ graft could re-program the fate of FNP neural
crest-derived mesenchyme, even at a very late stage in facial development.
FNP outgrowths occur at dorsoventral compartment boundaries
The immunohistochemical localization of quail cells had previously
established that FEZ grafts consisted of ectoderm with no adherent mesenchyme
(Fig. 2F). We now used QCPN
immunostaining to demonstrate conclusively that the dorsoventral molecular
boundaries corresponded to the initiation sites of FNP outgrowth. Boundaries
resulting from the juxtaposition of two dorsal domains (e.g.
Fig. 5A, blue arrow) were not
associated with sites of outgrowth and were instead characterized by the
seamless continuity of chimeric ectoderm
(Fig. 5B). The juxtaposition of
quail ventral ectoderm and chick dorsal ectoderm created a chimeric FEZ
(Fig. 5A), which resulted in an
ectopic outgrowth (Fig. 5D). In
only one location, where ventral FEZ abutted the dorsalmost region of the FNP,
did we fail to observe a predicted outgrowth
(Fig. 4J, question mark). The
reasons for this are unclear, but may be related to our previous observation
that Msx1 and Lfng were not induced in this dorsalmost
mesenchyme as they were in FEZ-associated mesenchyme
(Fig. 3O,U). Nonetheless, the
immunohistochemical data confirmed that unlike other regions of FNP ectoderm,
dorsal and ventral regions of the FEZ were sufficient to induce FNP
outgrowth.
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DISCUSSION |
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The establishment of the FEZ begins prior to the arrival of FNP neural
crest into the primordium. For example, Fgf8 is restricted to dorsal
FNP ectoderm; this expression domain is established at the time of neural tube
closure (Marcucio et al.,
2001). Barx1 and Pax6 are restricted to ventral
FNP ectoderm; their expression domains are evident in this tissue long before
neural crest cells are present in the FNP (R.S.M. and J.A.H., unpublished).
Thus, the segmented characteristics of the FNP ectoderm develop independently
of the presence of neural crest cells.
Our data indicate that stage 20 FNP ectoderm has the ability to re-specify
facial pattern (Fig. 4); this
patterning capacity is lost with time. Unpublished results from other
investigators suggest that cephalic ectoderm from early neurulas does not
exhibit any patterning activity (Couly et
al., 2002). We interpret these seemingly paradoxical findings as
an indication that the FEZ acquires the ability to specify FNP pattern
sometime between the conclusion of neurulation and upon arrival of neural
crest cells in the primordium. The acquisition of patterning ability over time
is a feature shared by other organizing tissues, including the zone of
polarizing activity in the limb bud
(Wilson and Hinchliffe,
1985
).
Recently, the pattern `of every given bone in the face' has been proposed
to be `pre-featured' in pharyngeal endoderm
(Couly et al., 2002). Although
the endoderm clearly influences patterning of the first pharyngeal arch
skeleton, it is improbable that this tissue contributes to patterning the
skeletal derivatives of the FNP. Cranial neural crest destined for the FNP
migrate over the forebrain rather than past the pharyngeal endoderm, making it
unlikely that signals from this tissue impact neural crest skeletal precursors
en route to the FNP. Once resident in the FNP, these same neural crest cells
are sandwiched between neural ectoderm of the forebrain and facial ectoderm,
rather than pharyngeal endoderm. Nonetheless, our data and those of others
(Couly et al., 2002
) indicate
that epithelia provide instructive cues that direct patterning within neural
crest-derived mesenchyme. This raises the obvious question of whether or not
neural crest cells from different axial levels are equivalent in their ability
to respond to such instructive cues.
Our data demonstrate that only a subset of neural crest cells can respond
to patterning cues from the FEZ. Neural crest cells that originate rostral to
rhombomere 3, which are devoid of Hox gene expression, respond to FEZ cues,
whereas neural crest cells from rhombomere 4, which are Hox-positive, are
unresponsive to FEZ cues. Pharyngeal endoderm exhibits the same ability to
pattern Hox-negative, but not Hox-positive neural crest populations
(Couly et al., 2002). Although
these observations are in accordance with the theory that a Hox code
establishes a type of pre-pattern within the pharyngeal skeleton
(Gendron-Maguire et al., 1993
;
Kanzler et al., 1998
;
Rijli et al., 1993
), they also
leave open the possibility that neural crest of the frontonasal, maxillary and
mandibular primordia are highly responsive to local patterning cues.
The FEZ directs dorsoventral patterning in the upper beak
skeleton
Changing the dorsoventral orientation of the FEZ graft changes the
dorsoventral orientation of the duplicated structures. Thus, FNP ectoderm not
only produces cues that pattern FNP skeletal elements, it also dictates their
orientation relative to the body axis. Based on our experimental results, we
formulated a model whereby the juxtaposition of dorsal and ventral compartment
boundaries specifies the dorsoventral pattern of the upper beak. This
dorsoventral boundary model is predicated on the work of others.
One model, based primarily on the work of Mangold
(Spemann and Mangold, 1924)
and the work of Meinhardt (Meinhardt,
1983
) proposes that the juxtaposition of differentially specified
tissues leads to the generation of morphogen. An equally feasible hypothesis
is that the juxtaposition of the same two tissues directly specifies cell fate
(Lecuit and Cohen, 1997
). In
either scenario, cells located at the boundary itself can respond in unique
ways to local cues because of their individual developmental histories. In the
FNP, we propose that these differentially specified tissues are dorsal (e.g.
Fgf8, Bmp4 and Wnt13 positive) and ventral (e.g.
Shh and Bmp2 positive) ectoderm. Interactions between the
Fgf, Bmp, Wnt and Shh pathways are well documented during limb bud and neural
tube development, and growing evidence indicates that these same pathways also
interact in the FNP (Barlow and
Francis-West, 1997
; Duprez et
al., 1996
; Hu and Helms,
1999
; Lee et al.,
2001
; Richman and Tickle,
1992
; Schneider et al.,
2001
).
If we apply the principles of a boundary/organizer model to our
experimental system, placing the graft into a dorsal compartment should result
in an ectopic FEZ (contained within the graft itself) and the generation of at
least one new intersection between ventral FEZ and dorsal host ectoderm
(Fig. 5). The question is
whether this new intersection acts as a FEZ. According to some boundary
models, this intersection would be the site of morphogen production, which
indirectly induces outgrowth. Our experimental data support this theoretical
prediction (Fig. 4I,O; Fig. 5D). Our model also
predicts that juxtaposing dorsal FEZ with dorsal host ectoderm would not
result in an outgrowth; this is also our experimental observation
(Fig. 5B). The ability of an
epithelium to alter dorsoventral patterning in the face is not without
precedence: pharyngeal endoderm can regulate the dorsoventral orientation of
the first arch skeleton (Couly et al.,
2002).
Epithelium or mesenchyme: which controls facial patterning?
Our data provide evidence that the instructive cues, which originate from a
discrete region of FNP ectoderm, pattern FNP neural crest mesenchyme. The
Hox-positive or Hox-negative status of the cells affects the interpretation of
these ectodermal signals.
Our experimental results challenge the long-held belief that the neural
crest is the source of patterning information in the face (reviewed by
Chambers and McGonnell, 2002).
In a number of developmental paradigms the ectoderm is responsible for
directing morphogenesis of neural crestderived tissues
(Barlow et al., 1999
;
Hardcastle et al., 1999
;
Sarkar et al., 2000
;
Sarkar and Sharpe, 1999
;
Tucker et al., 1999
). We show
that local environmental cues can direct morphogenesis of the upper beak. In
other experiments, we have recently shown that the particular response of the
neural crest is based on species-specific characteristics
(Schneider and Helms, 2003
)
and the rostrocaudal level from which the neural crest originates
(Noden, 1983
;
Serbedzija et al., 1991
).
In conclusion, the FEZ can direct outgrowth and dorsoventral pattern of the upper beak, but the precise shape of that upper beak undoubtedly depends upon patterning information inherent in the neural crest. Ultimately, the sculpting of a patterned tissue is the cumulative effect of stage-dependent reciprocal signaling events occurring between epithelia and mesenchyme. These experiments elucidate a new role for FNP ectoderm in regulating aspects of outgrowth and axis specification in the facial primordia.
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ACKNOWLEDGMENTS |
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Footnotes |
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