1 U 368 INSERM, Ecole Normale Supérieure, 46, rue d Ulm, F-75230 Paris Cedex 05, France
2 Laboratory of Molecular Genetics, National Institute of Child Health and Human Development, NIH, Bethesda MD, USA
3 Developmental and Cell Biology, University of California, Irvine CA 92697, USA
These two authors contributed equally to this work
*Author for correspondence (e-mail: rosa{at}wotan.ens.fr)
Accepted 27 June 2002
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SUMMARY |
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Key words: Neural crest, Fate, Cartilage, Endoderm, Patterning, casanova
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INTRODUCTION |
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Epithelial-mesenchymal interactions are crucial for the proper development of the pharyngeal region. For instance, pharyngeal muscles are specified by an interaction between neural crest-derived ectomesenchyme and head mesoderm (Noden, 1983; Schilling et al., 1996a
; Schilling and Kimmel, 1997
). The pharyngeal ectoderm of the most anterior arch in the mouse produces signals, including FGF8, essential for the differentiation of neural crest cells into chondrocytes and for the DV patterning of cartilage elements within this arch (Trumpp et al., 1999
). Similarly, Endothelin-1, expressed by both head paraxial mesoderm and pharyngeal epithelia, is crucial to the development of ventral pharyngeal arch cartilages (Kurihara et al., 1994
; Miller et al., 2000
). Epithelial-mesenchymal interactions also appear critical for the proper AP patterning of the pharyngeal arches. Heterotopic transplantation of entire hindbrain/neural crest segments had suggested that mesenchymal neural crest cells were prepatterned along the AP axis before leaving the neuroectoderm to give rise to the different cartilages and bones of the arches. However, heterotopic transplantation of single neural crest cells or small cell groups have suggested rather that AP identity of neural crest cells can be reprogrammed under the influence of cues provided by the environment (Trainor and Krumlauf, 2001
; Schilling et al., 2001
). Furthermore, Hoxa2 misexpression at postmigratory stages has demonstrated that mandibular crest can be reprogrammed after migration (Pasqualetti et al., 2000
).
Pharyngeal endoderm physically interacts with neural crest mesenchyme and might also play an important function in the control of neural crest fate and arch development. Probably because it is not easily accessible, however, its function in the pharyngeal region has been poorly defined. Extirpations of the most anterior (mandibular) pharyngeal endoderm or ectopic grafts of neural crest-derived ectomesenchyme with or without associated endoderm have been performed in amphibian, chick and mouse embryos (Graveson and Armstrong, 1987; Hall, 1980
; Seufert and Hall, 1990
). These experiments suggest that mandibular ectomesenchyme can only differentiate into cartilage when co-cultured or co-grafted with anterior (foregut, stomodeal or pharyngeal), but not with posterior (midgut or hindgut) endoderm. Whether or not pharyngeal endoderm is only involved in later stages of cartilage differentiation or has an earlier function in the control of neural crest fate and how this function is mediated at the molecular level is not understood at present. Pharyngeal endoderm also exhibits some degree of AP patterning, and recent evidence from grafts of foregut endoderm in chick suggests that this reflects a differential function of this tissue along the AP axis (Graham and Smith, 2001
; Couly et al., 2002
).
In vertebrates, endoderm and mesoderm are specified by Nodal-related signals, members of the transforming growth factor ß superfamily (Schier and Shen, 2000). Nodal activities are mediated by type I TGFß receptors ALK4 and ALK7 in mammals and most likely by their relative, Taram-A (tar) in zebrafish (Aoki et al., 2002a
; Reissmann et al., 2001
; Yeo and Whitman, 2001
). Activation of the Nodal pathway by expression of a constitutively active version of tar (tar*) leads to a respecification of early zebrafish blastomeres to an endodermal fate, consistent with the model that high levels of Nodal signalling are sufficient to direct cells to become endoderm (David and Rosa, 2001
; Peyrieras et al., 1998
). Downstream of nodal signalling, endoderm formation further involves the homeobox transcription factors Mixer/Bonnie and clyde (bon) and the recently identified Sox-related factor Casanova (cas) (Dickmeis et al., 2001
; Kikuchi et al., 2001
; Kikuchi et al., 2000
). Zebrafish embryos in which Nodal signals are inactive develop neither endoderm nor mesoderm (Feldman et al., 1998
) while, in contrast, bon or cas mutants form mesoderm but little or no endoderm (Alexander et al., 1999
; Aoki et al., 2002b
). In particular, cas mutants lack expression of all endodermal markers and derivatives. Interestingly, cas embryos are not rescued by activation of Nodal-related ligands or of the Tar cascade, consistent with its proposed function downstream. However, they provide a permissive environment for endoderm development since tar*-activated wild-type blastomeres can autonomously restore endoderm formation when grafted into cas embryos (David and Rosa, 2001
).
We have used cas and bon mutants to test whether or not pharyngeal endoderm is required for formation of the pharyngeal skeleton. We show that both mutants lack most of the ventral cartilage of the head skeleton and that these gene functions are required after cephalic neural crest migration, when crest normally contacts the endoderm. We fate map neural crest in cas and show that, in the absence of endoderm, cephalic neural crest cells remain as a cluster on the surface of the yolk sac and down regulate the expression of pre-chondrogenic markers. cas neural crest cells still have the ability to develop into cartilage when transplanted into wild-type embryos, showing that the cas gene is not required autonomously in neural crest cells but rather in their environment. Furthermore, endoderm can rescue head cartilage formation when reintroduced by grafting wild-type tar*-injected cells into cas embryos. Finally, we implicate FGF in signalling from endoderm to neural crest by demonstrating that endodermal expression of FGF3 is specifically required for the formation of the posterior, branchial arches. Altogether, our results demonstrate a requirement for pharyngeal endoderm and FGF signalling in the control of head neural crest fates and cartilage induction, and identifies FGF3 as the first endodermal signal with an AP restricted function in the pharyngeal region.
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MATERIALS AND METHODS |
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Fate mapping of chondrogenic neural crest cells
10 kDa DMNB-caged fluorescein (5 mg/ml) was injected into 2-cell stage embryos, then activated when embryos had reached the 5- to 7-somite stage in a region encompassing the dorsal and lateral neural tube (Bally-Cuif et al., 2000; Girdham and OFarrell, 1994
). The location of the labelled cells was analysed at 28 hours either by visual inspection or by immunodetection of fluorescein.
Grafting experiments
Donor embryos were injected at the 4-cell stage with FITC-dextran. At the 10-somite stage, labelled premigratory neural crest were transplanted into wild-type hosts (David and Rosa, 2001; Schilling et al., 1996a
). To restore endodermal derivatives in cas embryos, wild-type donors were injected with 80/1.2 pg GFP/Tar* RNA (or GFP alone as control) together with 120 pg nls-lacZ RNA or with 3% 10 kDa dextran biotin. At the sphere stage, 10-20 donor cells were grafted to the margin of the progeny of cas/+ heterozygotes. When grafted a this stage, cells from control donors do not contribute efficiently to endoderm (Aoki et al., 2002b
).
Morpholino oligomer injections
Morpholino oligomers obtained from Gene Tools Inc. were diluted in Danieaux solution. fgf3-morpholino (Shinya et al., 2001; Phillips et al., 2001
) was injected at the 1-cell stage or at the 16-cell stage at a concentration of 0.1 mM. fgf4 was injected at varying concentrations up to 0.5 mM. fgf3-Mo: 5'-CATTGTGGCATGGAGGGATGTCGGC; fgf4-Mo: 5'-TTCTAAAAGGAGTTGAAGACACCG.
Phenotypic analyses
In situ hybridisation and immunohistochemistry were done following standard protocols (Hauptmann and Gerster, 1994). Probes and antibodies used were: ctc (Bruneau et al., 1997
), dlx2 (Akimenko et al., 1994
), fkd6 (Kelsh et al., 2000
), fkd7 (Odenthal and Nusslein-Volhard, 1998
), foxA2 (Strahle et al., 1993
), hoxb2 (Yan et al., 1998
), Hu (Marusich et al., 1994
), nkx2.3 (Lee et al., 1996
), nkx 2.5 (Lee et al., 1996
) and rdr (Delot et al., 1999
), Zn5 (Trevarrow et al., 1990
). Cartilage was stained with Alcian Blue as described previously (Kimmel et al., 1998
). To monitor cell death, we used either Acridine Orange at 5 µg/ml (Delot et al., 1999
) or TUNEL analysis (Apoptag in situ kit, Intergen).
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RESULTS |
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To determine if the phenotype observed in cas results from a more general neural crest defect, we also analysed various other neural crest cells derivatives. Between 48-72 hours the number and distribution of melanocytes and mesenchyme migrating in the median fin folds are identical in cas homozygous embryos and their wild-type siblings (data not shown). Likewise, expression of fkd6, which labels premigratory cranial neural crest (12 hpf; data not shown) and later putative glial precursors at 24 hpf (Kelsh et al., 2000), as well as Hu expression in cranial and trunk sensory neurons, also appear normal in cas homozygous embryos (Fig. 1P-S). Conversely, and consistent with cartilage defects, expression of collagen2a in the forming arches at 48 hpf is absent in cas mutants (data not shown). Taken together, these results suggest that the cas mutation specifically affects a chondrogenic subset of neural crest in the head.
Fate of chondrogenic neural crest cells in cas embryos
The progressive loss of dlx2 expression in cas mutants could result from a fusion of neural crest streams, local downregulation of gene expression or death of cells populating streams II and III. To distinguish between these possibilities, we followed cranial neural crest morphogenesis in cas mutants. Morphological inspection with Nomarski optics at 24 hpf revealed two abnormally large, bilateral arch primordia flanking the head, one anterior (Fig. 2A,B) and one posterior to the otic vesicle in the positions of streams II and III. At higher magnification, cells in the anterior primordium appeared disorganised unlike wild-type embryos in which neural crest cells align in vertical rows (not shown). We also observed an accumulation of mesenchymal cells in the position of stream I, immediately posterior to the eye.
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To confirm this, we photoactivated DMNB-caged fluorescein in larger stretches of crest at 12 hpf, encompassing territories both anterior and posterior to the otic vesicle and co-localized the lineage tracer (orange) (Fig. 2E-H), with the ectomesenchymal marker dlx2 at 28 hpf (purple) (Fig. 2G,H). In contrast to wild-type embryos (Fig. 2G), stream III is dlx2-negative in cas mutants (Fig. 2H). Thus in cas, precursors of the branchial arches migrate ventrally, to reach a position over the yolk that is in register with their normal AP fate, but they lose dlx2 expression. At similar stages, stream III cells continue to express hoxb2 and hoxb3, another indication that they retain their correct AP positional value (Fig. 2I-L). To determine if neural crest cells in these abnormal arch primordia in cas die, we analysed cell death patterns in wild-type and cas homozygous embryos using both Acridine Orange staining (Fig. 2M,N) and TUNEL analysis (Fig. 2O-Q). Strikingly, while little cell death is observed in arches between 24-48 hpf in wild type, significant cell death is observed in this region in cas homozygous embryos. This cell death is first detectable at 24 hpf and becomes more pronounced by 30 hpf, occurring throughout the mediolateral extent of the arch (Fig. 2Q). Thus, at least some ectomesenchymal neural crest cells require cas function for maintaining their identity and survival.
The requirement for cas in head cartilage formation is cell non-autonomous
cas is a sox-related transcription factor required autonomously within endoderm cells for their development and differentiation. Although no expression of cas can be detected in neural crest cells (Dickmeis et al., 2001; Kikuchi et al., 2001
), cartilage defects might reflect an autonomous requirement for cas/sox expressed at a very low level. To exclude this possibility, we used mosaic analysis to test the capacity of cas neural crest cells to differentiate into cartilage when transplanted into wild-type hosts. Chondrogenic cranial neural crest that forms the jaw (mandibular arch) has been mapped at 12 hpf (Schilling and Kimmel, 1994
) to the most dorsal tiers of premigratory neural crest cells in an oblong primordium located between the eye and the otic vesicle. FITC-dextran-labelled cranial neural crest cells were grafted from this location in cas mutants into the same chondrogenic region of wild-type host embryos and their fates were followed until day 3 (Fig. 3B). Most of these cas mutant cells differentiated into typical neural crest derivatives, notably contributing with high frequency to the cartilage elements of the mandibular and hyoid arches (50%, n=12; Fig. 3C,D). Controls in which wild-type cranial neural crest cells were transplanted into wild-type hosts formed cartilage at a similar frequency (56%, n=16). In contrast, wild-type cells transplanted into cas homozygous embryos never differentiated into cartilage (0%, n=15). These results demonstrate that cranial neural crest cells in cas have the ability to develop into cartilage when placed into a wild-type environment and thus cas activity is required non-autonomously. cas must be required in the premigratory or migratory environment of these neural crest cells to control their participation in pharyngeal cartilage formation. An attractive candidate for the source of such environmental influences is the endoderm because, (i) this tissue is absent in cas, (ii) neural crest cells in the arches contact pharyngeal endoderm prior to chondrogenesis (Schilling and Kimmel, 1994
), and (iii) endoderm has been shown to influence the differentiation of chondrocytes in amphibians (Seufert and Hall, 1990
). To test this idea, it was essential to restore endoderm in cas homozygous embryos and analyse its consequences for the formation of the viscerocranium.
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fgf3 is required within the endoderm to control the fate of posterior cranial neural crest
Expression of fgf3 in the neural tube and/or in the pharyngeal endoderm could be responsible for the phenotypes of fgf3 morphants. To determine which of these two sites of expression is essential for the control of chondrogenic crest fate, we performed two series of experiments. We first created chimaeric fgf3 morphants by injecting the morpholino into one marginal cell of a 16-cell-stage embryo. Using this procedure, progeny of the injected cells populate mostly mesoderm- and endoderm-derived tissue (Peyrieras et al., 1998). Such a local knock-down led to asymmetric embryos lacking posterior arches only on the morpholino-injected side and this phenotype was strictly correlated with the localisation of morpholino-positive cells in the pharyngeal pouch region (Fig. 6F). These results indicate that fgf3 activity is required within pharyngeal endoderm/mesoderm for the formation of branchial arches 1 to 4. To confirm this and to determine whether fgf3 expression is required in mesoderm or more likely in endoderm, we analysed the restoration of pharyngeal arch formation in cas embryos by transplantation of tar*-induced endoderm from fgf3 morphants. At 4 days, this led to an efficient restoration of anterior arches (mandibular and hyoid) but never rescued branchial arches, demonstrating that fgf3 expression is required in the endoderm for formation of posterior arches (Fig. 6H and Table 1).
Altogether, our results show that fgf3 expression in pharyngeal pouches is crucial for the control of posterior chondrogenic neural crest fate and pharyngeal arch formation. Interestingly, they also suggest that even if endoderm is necessary for the formation of all arches, this must be mediated by other signals in addition to FGFs in the anterior arches.
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DISCUSSION |
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Previous reports had suggested that endoderm is important in pharyngeal cartilage patterning. For instance, pharyngeal skeletal defects throughout the arches in the van gogh mutant in zebrafish correlate with defects in pharyngeal endoderm (Piotrowski and Nusslein-Volhard, 2000). Similarly, the use of a pan-RAR antagonist in mice led to defects in specification of arches 3 and 4 that the authors attributed to a disruption of signalling from the endoderm associated with these segments (Wendling et al., 2000
). However, in the absence of mosaic analysis in both cases, the causal relationship between endodermal and skeletal defects remained speculative. Recent mosaic analyses in the chick have, however, provided stronger evidence that the endoderm provides AP positional information to the developing skeleton (Couly et al., 2002
). In the present work, by means of genetic ablation and reintroduction of endoderm, we provide direct evidence for a crucial function of endoderm in the control of pharyngeal arch cartilage development. Whether or not endoderm acts directly on neural crest cells or requires an intermediate signal via neighbouring tissues cannot be ascertained at this point. However, the close spatial proximity between neural crest cells and endoderm within an arch (Trainor and Tam, 1995
; Miller et al., 2000
) as well as the coincidence between the early defects in neural crest-specific gene expression in cas mutants at stages when these cells first contact pharyngeal pouches (Schilling and Kimmel, 1994
), argue in favour of a direct signal.
Endoderm controls the fates of chondrogenic crest cells
Until now, it was not clear whether endoderm had only a late function in controlling cartilage differentiation or acted at an early stage for correct migration of neural crest cells, for the maintenance of their identity, and/or for their survival. Our results suggest a role for endoderm in several of these early steps.
Endoderm is required for midline convergence of cranial neural crest cells
Arch precursor/neural crest cells normally stream from their origins adjacent to the hindbrain and migrate ventrally to surround the pharynx. In zebrafish initial streams form normally in the absence of endoderm, as shown by the expression of dlx2 in cas mutants, suggesting that this tissue does not provide cues essential for initial migration. However, crest cells then accumulate in disorganized masses in cas mutants, and fail to migrate further ventrally or medially. Restoration of endoderm in cas mutants by transplantation results in the proper positioning of arch cartilage elements, strongly suggesting that these later aspects of crest migration are also restored. Thus endoderm appears important for convergence of cartilage precursors below the head. One possibility is that midline pharyngeal endoderm provides attractive signals for arch cartilages/neural crest precursors. Alternatively, endoderm may serve as a substrate for the migration of neural crest cells, and/or may passively displace adherent neural crest cells in the course of its own morphogenetic movement towards the midline (Warga and Nusslein-Volhard, 1999). Several bilateral organ anlage including, arch cartilage precursors, the precursors of the heart, blood vessels, kidneys and blood fail to converge or they exhibit delayed convergence toward the midline in endoderm deficient mutants such as cas and oep (Alexander et al., 1999
; Peyrieras et al., 1998
). Convergence of heart precursors can also be rescued by restoring endoderm, therefore strongly supporting the notion that endoderm has a key function in the control of convergence movements of many tissues toward the midline, a process essential for their morphogenesis (David and Rosa, 2001
; Peyrieras et al., 1998
).
Endoderm is required for the maintenance of chondrogenic crest cells
Soon after they have reached the yolk surface, neural crest cells in cas mutants downregulate dlx2 and dlx3 expression suggesting that endoderm is required to maintain expression in these cells. In support of this interpretation, mouse mandibular arch mesenchyme cultured by itself initially requires signals released from the adjacent oral epithelium to maintain the expression of crest-specific markers, though this later becomes epithelium-independent (Ferguson et al., 2000). With the markers available, we find no evidence that, in the absence of endoderm in cas, crest cells change their fates from chondrogenic to non-chondrogenic crest fates. Rather, by 30 hpf, crest cells in the arches undergo a period of extensive cell death, which may explain the lack of pharyngeal arch cartilage in the larva. Death may occur as a result of a failure in chondrogenic specification leading to the subsequent death of this subpopulation (fate mapping evidence suggests cartilage precursors are specified as early as premigratory stages) (Schilling and Kimmel, 1994
) or, alternatively, cas and/or endoderm may have a more general requirement for crest cell survival in arches, including those cells that would form cartilage.
Endoderm and the process of segmentation
Chondrogenic neural crest cells migrate in distinct streams to generate distinct segmental structures in each arch (reviewed by Trainor and Krumlauf, 2001). Segmental migration has been proposed to reflect the segmental origins of crest cells in the hindbrain which then confers segmental patterning on the pharyngeal region (Noden, 1983
). However, recent evidence from neural crest ablation studies in chick have demonstrated that segmentation of the pharyngeal endoderm does not depend on neural crest (Veitch et al., 1999
). Likewise, our studies suggest that initial segmental migration of neural crest does not require cues from the endoderm. We use cell tracing studies to show that in the absence of endoderm in cas mutants, neural crest in the primordia of the mandibular and hyoid arches do not fuse and remain separate. Strict segmental lineage restrictions in zebrafish are already established at the onset of migration for these arches and probably result, at least in part, from factors intrinsic to the neural crest (Schilling and Kimmel, 1994
). Endodermal morphogenesis may have some influence on the patterning of cranial crest once it reaches the arches, as suggested by recent analysis of the van gogh mutant (Piotrowski and Nusslein-Volhard, 2000
). In support of this idea, we found that posterior neural crest cells, which normally split to form the five branchial arches, remain as a cluster in cas mutants suggesting that endodermal pouches are required to subdivide the branchial arches.
Molecular nature of the endodermal signal
One further challenge is to identify signals provided by the endoderm to neural crest cells. Several pieces of evidence support a major function of FGF signalling in the control of cranial neural crest fate and pharyngeal cartilage development. First, several FGFs and their receptors are expressed in the pharyngeal region (Launay et al., 1994; Mahmood et al., 1995
; Wall and Hogan, 1995
; Shinya et al., 2001
; Kudoh et al., 2001
; Furthauer et al., 2001
). Second, FGF signalling is active in this region in amphibians following neural crest cell migration (Christen and Slack, 1999
) and required to some extent for arch patterning in zebrafish and in mice (Roehl and Nusslein Volhard, 2001
; Trumpp et al., 1999
). We show that general inhibition of FGF signalling by Su5402 during arch morphogenesis prevents arch cartilage formation. Su5402 treatments also cause earlier downregulation of dlx2 and marked neural crest cell death, a situation strikingly reminiscent of the phenotypes observed in endoderm-deficient mutants.
Our results also implicate fgf3 as an important regulator of cartilage development. Indeed, general disruption of fgf3 function in fgf3 morphants inhibits formation of posterior arches (though it has little effect on the most posterior, 5th branchial arch, which is often unaffected in arch mutants) (Schilling et al., 1996b). However, fgf3 is expressed both in the anterior neuroectoderm, from which cranial neural crest originates and in pharyngeal endoderm (Furthauer et al., 2001
) (this work). To further define which of these sites is important for arch formation, we reduced fgf3 function locally by creating chimaeric morphants. Consistent with a requirement for fgf3 signals from the endoderm and not ectoderm, embryos harbouring fgf3 morpholinos specifically in the cranial mesendoderm also exhibit a reduction or absence of branchial arch cartilages. In addition, cas mutants lack fgf3 expression in the endoderm but not neuroectoderm. Altogether, these results suggest that fgf3 is an essential signal from pharyngeal endoderm that induces skeletogenesis from the cranial neural crest.
Intriguingly, whereas endoderm and FGF signalling appear to be required for the whole set of arch cartilages, loss of fgf3 function in morphants specifically prevents the formation of the posterior (gill-bearing) but not the anterior (mandibular and hyoid) arches. Likewise, transplantation of fgf3 morphant-derived endoderm into cas embryos only rescues the formation of the mandibular and hyoid arches but not the gills. This differential requirement for fgf3 function, together with the fact that fgf3 is maintained in the posterior but not the most anterior (mandibular) arch endoderm, suggests that pharyngeal endoderm may provide distinct cues along the AP axis, which could participate in the control of the formation of the distinct types of cartilage elements, together with patterning information conveyed by chondrogenic neural crest cells at the time they colonise the pharyngeal pouches.
When is Fgf3 required? Previous studies in quail have suggested a late function of FGF2 in promoting chondrogenesis (Sarkar et al., 2001). However, both the early expression of fgf3 in pharyngeal endoderm and reduction of dlx2 expression at 30 hpf in fgf3 morphants argue in favour of an earlier function for FGF3, in specification and survival of chondrogenic crest cells. Consistent with this idea, disruption of fgf8 function in the ectoderm of the first branchial arch in mice disrupts survival of chondrogenic crest cells (Trumpp et al., 1999
). FGFs can function in vitro as survival factors for a wide variety of cell types, including crest cells (reviewed by Szebenyi and Fallon, 1999
). Its absence in endoderm-deprived mutants could thus directly account for the significant increase in cell death observed in these embryos.
Interestingly, whereas fgf3 is necessary for posterior arch formation, it does not seem sufficient to induce these arches since transplants of cells expressing fgf3 in the pharyngeal region of cas embryos does not rescue gill arch formation nor dlx2 expression (data not shown). This strongly suggests that endoderm provides other diffusible cues also required for pharyngeal arch formation, a possibility consistent with the fact that FGFs have been shown to act in synergy with other diffusible substances in head morphogenesis (Schneider et al., 2001). Alternatively, signalling from endoderm to neural crest cells might also involve additional epithelial mesenchymal interactions, including direct cell-cell contacts. Thus, an exciting challenge in the future will be to identify other cues provided by the endoderm, and the way they help organise the pharyngeal arch region.
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ACKNOWLEDGMENTS |
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