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Neural Crest Cell Plasticity: Size Matters

and *.

* Corresponding Author: Stowers Institute of Medical Research, 901 Volker Blvd., Kansas City, Missouri 64110, U.S.A. Email:

Patterning and morphogenesis of neural crest-derived tissues within a developing vertebrate embryo rely on a complex balance between signals acquired by neural crest cells in the neuroepithelium during their formation and signals from the tissues that the neural crest cells contact during their migration. Axial identity of hindbrain neural crest is controlled by a combinatorial pattern of Hox gene expression. Cellular interactions that pattern neural crest involve signals from the same key molecular families that regulate other aspects of patterning and morphogenesis within a developing embryo, namely the BMP, SHH and FGF pathways. The developmental program that regulates neural crest cell fate is both plastic and fixed. As a cohort of interacting cells, neural crest cells carry information that directs the axial pattern and species-specific morphology of the head and face. As individual cells, neural crest cells are responsive to signals from each other as well as from non-neural crest tissues in the environment. General rules and fundamental mechanisms have been important for the conservation of basic patterning of neural crest, but exceptions are notable and relevant. The key to furthering our understanding of important processes such as craniofacial development will require a better characterization of the molecular determinants of the endoderm, ectoderm and mesoderm and the effects that these molecules have on neural crest cell development.


The neural crest is a population of migratory cells that arise transiently along the dorso-lateral margins of the closing neural folds during the neurulation stage of embryogenesis in vertebrates. Neural crest cells give rise to a remarkable array of cell types and contribute to a striking number of tissues and organs of the vertebrate body during embryonic development. In the trunk, neural crest cells produce neurons, glial cells, secretory cells and pigment cells—contributing to the peripheral nervous system, enteric nervous system, endocrine system and skin. Cranial neural crest cells exhibit an even more surprising diversity of derivatives, giving rise to pigment cells, nerve ganglia, smooth muscle, and connective tissue, as well as most of the bone and cartilage of the head and face (Fig. 1).1,2

Figure 1. Migratory neural crest cells give rise to bone and cartilage of the head and face.

Figure 1

Migratory neural crest cells give rise to bone and cartilage of the head and face. A) Coloured scanning electron micrograph of head region of a mouse embryo at 8.0 days of development. Neural crest cells (represented by green dots) are induced to form (more...)

Neural crest cells clearly contribute to many critical tissues and systems but it is the major role that neural crest cells play in building the vertebrate head and face that is particularly significant. The acquisition of neural crest cells, which drove evolutionary development of the head, is considered a key factor in the origin and evolution of vertebrates.3 The important evolutionary contribution of the neural crest is clearly evident in the remarkable diversity of avian beaks. Different species of birds exhibit striking differences in the shape, size and function of their beaks. Yet despite this amazing morphological diversity, the beak in each avian species is developmentally derived from comparable tissues, with the cartilage and connective tissue being formed primarily by neural crest cells.

Proper head and facial development requires the intricate integration of multiple distinct tissue types such as ectoderm, endoderm, mesoderm and neural crest. One of the defining features of craniofacial development is that it is an extraordinarily complex process that is characterized by massive active cell relocation (during neural crest cell migration) as well as passive displacement (head flexure). Given the multipotency of neural crest cells, their migratory character, and the importance and diversity of structures to which they contribute, the nature of the patterning program that directs neural crest differentiation is a key question in vertebrate developmental biology. Proper development of an embryo requires the patterning of progenitor cells to produce structures, such as the bones of the inner ear for example, of appropriate morphology in defined axial positions. Therefore, of particular interest is the question of whether neural crest cells play an instructive role and direct the patterning of craniofacial development or whether they exhibit plasticity and differentiate according to cues they receive from their environment. This question has been a subject of intensive research and debate over many years, with convincing arguments that neural crest cells govern species specific morphogenesis of the head and face and that the specification of neural crest cells is regulated by tissue specific environments.

The focus of this review is to firstly, examine the evidence concerning the instructive or responsive nature of neural crest patterning with the goal of elucidating factors and contexts that influence the plasticity and determination of this remarkable cell type. Secondly, we highlight the extraordinary complexity of the 3-dimensional tissue interactions that regulate normal craniofacial morphogenesis.

Hindbrain, Hox Genes and Axial Identity

The cranial neuroepithelium can be divided into forebrain, midbrain and hindbrain regions, each of which is a source of migrating neural crest cells. Neural crest cells do not appear to migrate randomly, rather they follow precise, species and region specific pathways moving sub-ectodermally over the surface of the mesoderm.4 In the head, neural crest cells typically migrate in discrete segregated streams, the pattern of which is highly conserved in vertebrate species as disparate as amphibians, teleosts, avians, marsupials and mammals (for review see ref. 5). Briefly, forebrain and rostral midbrain neural crest cells colonize the frontonasal and periocular regions. Caudal midbrain derived neural crest cells populate the maxillary component of the first branchial arch. The hindbrain is divided into seven distinct segments known as rhombomeres and neural crest cells emigrate from each rhombomere, but predominantly from rhombomeres 2, 4 and 6 in discrete segregated streams that populate the first, second and third branchial arches respectively.6

Exquisite fate mapping analyses, particularly in avians, have revealed that neural crest cells derived from each region of the cranial neural plate and in particular from each individual rhombomere generate specific parts of the craniofacial complex including unique components of the viscero- and neurocraniums as well as the peripheral nervous system.2,7,8 For example, neural crest cells that populate the maxillary and mandibular prominences of the first branchial arch form the upper and lower jaws respectively. In contrast neural crest cells that migrate into the second branchial arch give rise to elements such as the retroarticular process, columella and facial/vestibular cochlear nerve. The segmental organization of the hindbrain therefore, is important for the proper organization of the cranial ganglia, branchiomotor nerves and pathways of neural crest migration and as such is a conserved strategy used by vertebrates to establish the foundations or the blueprint of craniofacial development.9-18 Hence the hindbrain is one key source of patterning information for the migrating neural crest cells during early craniofacial development.

There are several families of genes whose patterns of expression are restricted to different segments of the brain and to specific rhombomeres within the hindbrain.19 Of particular interest are the Hox genes, a family of evolutionarily conserved transcription factors that play important roles in axial patterning.20 Interestingly, within the hindbrain, rhombomere segments are distinguished by specific patterns of overlapping Hox gene expression.16,17,21 Individual members of the Hox gene family are expressed in either single (e.g., Hoxb1 in rhombomere 4) or multiple overlapping segment domains (Hoxa2, Hoxb2, Hoxa3, Hoxb3), with distinct anterior limits of expression such that the combinatorial Hox code expressed by each rhombomere regulates its segmental identity.17,20,22-29

In addition to their expression in the neural tube, the segment-defining Hox genes are also expressed in neural crest derivatives within the ganglia and branchial arches in a manner that reflects the specific Hox pattern of the rhombomeres from which they originated.16,21,30-34 For example, Hoxa2 and Hoxb2 are expressed in the hindbrain up to an anterior limit that corresponds with rhombomere 3. These same two Hox genes are expressed in the vii/viii ganglion complex and the mesenchyme of the second and third branchial arches, which are derived from neural crest that emigrate from rhombomere 3 and more posteriorly. Similarly, within the hindbrain, Hoxa3 and Hoxb3 are expressed up to an anterior limit that coincides with rhombomere 5 and they are also expressed in third and fourth branchial arch neural crest cells and the ix/x ganglion complex.

Proper segmental restriction of Hox gene products is critical for normal craniofacial development. Ectopic expression of Hox genes outside their segmentally restricted domains causes defects in development of the craniofacial skeleton.35-37 Similarly, null mutations in mice have revealed the particular importance of Hoxa2 and Hoxa3 for patterning the branchial arch skeleton during craniofacial development.38-42 Neural crest cells that emigrate from the forebrain and midbrain, which give rise to distinct skeletal components of the upper face and jaw, do not express any Hox genes. This Hox-negative neural crest is necessary and sufficient for development of the facial skeleton43 and ectopic expression of Hox genes within the normally Hox-negative forebrain and midbrain neural crest disrupts cranioskeletal development.37 These results imply that a Hox code and axial patterning are important components of the regulatory mechanisms that govern normal neural crest cell development and craniofacial morphogenesis.

Environment Influences Neural Crest/Neural Crest Influences Environment

One mechanism that has been hypothesized to describe neural crest cell development and craniofacial patterning is the neural crest cell preprogramming model (for review see ref. 44). This model essentially consists of two important components. Firstly, neural crest cells are programmed prior to their emigration from the neural tube and secondly that neural crest cells control the patterns of cell differentiation around them. This model was based largely on two pieces of experimental evidence. The first is that the same combinatorial and rhombomere specific domains of Hox gene expression observed in the hindbrain were emulated by hindbrain-derived migrating neural crest cells. For example, rhombomere 4 expresses Hoxb1, Hoxb2 and Hoxa2 as do neural crest cells derived from rhombomere 4 that subsequently populate the second branchial arch. That the pattern of Hox expression in neural crest derivatives mirrors the pattern of expression in the neural tube from which the neural crest were derived suggested that segmental identity of neural crest could be preprogrammed within the neural folds and maintained passively as the cells migrate into the branchial arches.

The second piece of evidence came from a landmark study in which presumptive first branchial arch neural crest cells were grafted in place of more posterior hindbrain segments. These grafts resulted in duplications of the proximal first arch facial skeletal elements such as the squamosal, pterygoid, angular and quadrate bones in avian embryos.2 Interestingly, the muscle alignments and attachments associated with these ectopic jaw structures were typical of the first arch and not of the second arch tissues from which they were derived. This indicated that myogenic populations and other cell types receive spatial cues from the invading neural crest-derived connective tissue.2

Collectively, these observations prompted the model that neural crest cells acquire their genetic identity and regional fate specification before they emigrate from the neural tube. The patterning information acquired in the neural tube is then passively transferred to the periphery of the head and body by the neural crest cells where it directs the development not only of tissues derived from the neural crest cells themselves but surrounding myogenic and connective tissues as well.

Contradictory to this model however is substantial evidence in numerous species that Hox gene regulation in the neural tube and neural crest are independently controlled and can be dissociated from one another. The evidence is clearest in relation to the regulation of Hoxa2 which is critical for second branchial arch neural crest cell patterning.38,39 Hoxa2 is expressed in the hindbrain of vertebrate embryos up to an anterior limit that correlates with rhombomere 2. However neural crest cells derived from rhombomere 2 never express Hoxa2, implying that neural crest cells are not preprogrammed or specified prior to their emigration from this particular axial level of the neural tube.

However dissociation of Hox regulation between hindbrain and neural crest is also observed at other axial levels within the neural tube. Transgenic analyses of Hoxa2 in mice have revealed distinct cis-regulatory elements that mediate expression specifically within the caudal hindbrain or the neural crest.45-47 The transcription factor AP-2 α is one of the key players regulating Hoxa2 expression in second branchial arch neural crest cells. An AP-2 α specific binding element has been uncovered in the 5' regulatory region of Hoxa2 and mutations in this binding element eliminate Hoxa2 expression from second branchial arch neural crest cells.47 In contrast, the expression of Hoxa2 in rhombomere 4, from which the majority of second branchial arch neural crest cells are derived, was unperturbed and maintained at a high levels.

Furthermore, the differences in Hox regulation between neural crest and hindbrain neural tube are particularly evident in the analyses of embryos that lack AP-2 α function. AP-2 α is required in mice and zebrafish for survival and differentiation of certain subsets of neural crest emigrating from the hindbrain and spinal cord.48-52 In mice, mutation of the AP-2 α gene compromises expression of Hoxa2 in the neural crest but not in the hindbrain.47 Similarly, in zebrafish mutants such as montblanc and lockjaw, which disrupt the AP-2 α gene, Hox expression is dramatically reduced in second branchial arch populations of migratory neural crest but is not affected in the hindbrain regions from which the cells emigrated.51,52

Neural crest cell and hindbrain patterning are also independent from one another with respect to sensitivity to certain perturbations. Appropriate patterning of the neural crest-derivatives in the second branchial arch can be compromised by a reduction in Hoxa2 expression of only ˜50% whereas patterning of the anterior hindbrain remains relatively unaffected even when Hoxa2 expression is reduced to as little as 20% of normal levels.42 Conversely, retinoic acid treatment can induce phenotypic changes in the segmental identity of the hindbrain without affecting the derivatives of the neural crest.53 Thus, neural crest cells and the hindbrain from which they are derived differ both with respect to the regulation of Hox expression and also to the extent to which Hox gene products are required for their specification. Taken together these data compellingly argue that migratory neural crest cells do not simply carry an axial specification pattern programmed within the neural tube.

Neural Crest Plasticity Is Influenced by Graft Size and Developmental Age

Further convincing evidence that neural crest cells are not necessarily autonomously preprogrammed was revealed by neural crest cell transplant experiments in mouse and zebrafish that demonstrated the influence of environment on engrafted neural crest cells.54,55 Importantly, the fish and mouse experiments revealed a possible explanation for the seemingly contradictory instructive and responsive nature of neural crest cells. The key factor of the mouse and zebrafish studies is that they involved transplantation of relatively small numbers or even single neural crest cells. In contrast, early transplant experiments between chick and quail embryos typically involved transposition of relatively large numbers of cells, which led to conflicting ideas about the autonomy or plasticity of neural crest cells. Avian grafts of whole rhombomeres or larger neural tube segments involve relocation of hundreds or thousands of cells.

In the mouse system, a combination of lineage tracing and genetic markers were utilized to show that the Hox gene axial identity of neural crest cells translocated from the second branchial arch to first branchial arch environments could be dictated by new environment rather than the origin of the transplanted tissue.54 Interestingly, grafted cells that remained in coherent groups within the neural tube after transplantation, autonomously maintained their original Hox gene axial patterning information. Surprisingly, individual cells that dispersed from the cohort and remained within the confines of the neural tube adapted their Hox gene axial patterning information to fit with their new location. Specifically, groups of cells that maintained contact with their original community of cells retained Hox expression pattern of their original presumed fate and cells that became isolated from their community of grafted cells altered their Hox expression to a pattern appropriate for their new environment. Dispersed neural crest cell populations lack the strong cell community effects characteristic of individual rhombomeres that help to maintain segmental hindbrain identity. The autonomy observed in neural tube cells versus the plasticity uncovered in neural crest cells reflects the fact that neural tube cells typically exist in tight association with one another whereas neural crest cells migrate as a dispersed population. These results suggested that craniofacial development is not patterned by autonomous preprogrammed neural crest cells but instead is regulated by cellular interactions including neural crest cell interactions with each other as well as interactions with non-neural crest tissues in the branchial arch environments.56

The effect of graft size on neural crest plasticity was further emphasized by experiments in zebrafish in which neuroepithelial cells were transplanted as single cells or small groups of cells.55 As in the mouse experiments, the translocated zebrafish neuroepithelial cells were regulated, in some examples by their original position and in other instances by the environment into which the cells had been grafted. Again, the degree of plasticity of the transplanted neural crest cells correlated with the size of the tissue transplanted. When small grafts of 10 or fewer cells were transposed, plasticity of Hox gene expression was observed in all cases. When larger groups of up to 30 cells were translocated, cells at the center of an undispersed group maintained their original Hox expression while cells at the periphery of the graft exhibited plasticity. The neural crest cells that were derived from transplanted neuroepithelium always exhibited plasticity of axial identity to the extent that they incorporated into elements of the craniofacial skeleton that were typical of their new location.

That individual grafted cells are influenced by their new environment whereas large clusters of cells that remain in a coherent group are resistant to reprogramming strongly implicates interactions of neural crest cells with each as well as the tissues they contact during their migration in the regulation of their patterning and morphogenesis. In support of this idea, timelapse imaging of avian embryos has revealed that individual neural crest cells maintain contact with each other and the adjacent mesoderm, ectoderm and endoderm environments via extensive and dynamic filopodial and lamellipodial connections.57

As might be expected, the plasticity of neural crest cells becomes restricted with developmental age. In the zebrafish transplantation experiments described above, plasticity of Hox expression diminished as developmental age increased. When neural crest cells were transplanted at the 5 somite stage, Hox expression was regulated by the new environment in more than 80% of transplanted cells. In contrast, when neural crest cells were transplanted at the 15 somite stage, Hox expression was altered by transplantation in only 40% of the cells.55 Corresponding temporal restrictions in cell fate are also observed when mature avian neural crest cells are transplanted back into the immature environment of much younger avian embryos.58

The ability of transplanted neural crest cells to adopt fates appropriate to their new location provides clear evidence that prior to their migration from the neural tube, the program specifying their axial identity remains flexible and cells remain responsive to their environment. However, these results seem contradictory to those obtained when rostral hindbrain neuroepithelium was transplanted more caudally in avian embryos resulting in jaw duplications.2 How can the convincing evidence that neural crest fate is influenced by the environment into which the cells migrate be reconciled with the evidence from classic quail to chick chimera transplantation experiments that promoted the idea that neural crest cells are autonomously programmed while still in the neural tube?

An often ignored aspect of Drew Noden's landmark study is that in addition to forming duplicated first branchial arch jaw skeletal structures, the transplanted neural crest cells also contributed to the formation of relatively normal second arch skeletal elements, an indication that the patterning of some of the transplanted progenitor cells was directed by their new environment. Furthermore, within the same study transplantation of presumptive frontonasal neural crest in place of hindbrain neural crest and transplantation of first branchial arch neural crest cells each produced similar duplicated first arch structures. This is despite the fact that frontonasal neural crest cells do not normally give rise to bones such as the squamosal, pterygoid and quadrate. Thus, the same inappropriate duplicated jaw skeletal elements could be formed by two distinct populations of neural crest cells translocated from two completely different axial levels. Drew Noden was astutely cautious in the interpretations of his results because of these observations of neural crest cell plasticity and concluded that “these results indicate there are no irreversibly specified frontonasal, maxillary and trabecular segments of the premigratory neural crest”.2

One possible explanation for how these two different axial populations of avian neural crest cells give rise to similar jaw structures in ectopic transplants could reside in their proximity adjacent to the isthmus.59 The isthmus is a clear, well-characterized neuromeric landmark which lies at the junction between the midbrain and hindbrain. Unbeknown in the 1980s, the isthmus is an important organizing centre that regulates patterning within the hindbrain and hindbrain tissues, specifically restricting Hox gene expression in the anterior hindbrain.60-62 As described above, Hox genes are critical determinants of neural crest and branchial arch patterning. Given that the isthmus is contiguous with both the presumptive frontonasal and anterior hindbrain neural crest cell populations, it seems likely that isthmus organizer patterning was highly influential in the jaw duplications that were observed by Noden. In support of this idea, posterior transplantations of just the isthmus in place of presumptive second branchial arch neural crest cells can also lead to the formation of duplicated jaw structures such as the quadrate.59

At the level of gene expression, the posterior transplantations of the isthmus led to the suppression of Hoxa2 in the second branchial arch. This is significant because Hoxa2 is a key regulator of second branchial arch patterning. In Hoxa2 null mutant mice, the identity of the second branchial arch is transformed into that of a first branchial arch such that the mice exhibit duplications of jaw skeletal elements.38,39 The similarity between the jaw duplications observed in avian and mouse studies provocatively suggested that the transplantations of avian neuroepithelium from distinct axial levels, each of which possibly included some isthmus tissue, effectively created a conditional knockout of Hoxa2 in the second branchial arch thereby transforming its identity into that of a first branchial arch. These results demonstrate the plasticity and adaptability of neural crest cells and highlight the effects of local signaling centers on anterior-posterior patterning.63

The idea that neural crest cells exhibit an inherent plasticity or adaptability that can be regulated by their microenvironments is supported by other classic transplantation experiments that utilize regional differences in trunk neural crest cell derivatives. For example, parasympathetic neurons are formed by the vagal neural crest (at the level of somites 1-7). These neurons, known as cholinergic neurons, line the gut and produce the neurotransmitter acetylcholine. Sympathetic neurons form in the thoracic region from trunk neural crest cells. These cells produce norepinephrine and are called adrenergic neurons. When chick vagal and thoracic neural crest cells are reciprocally transplanted or exchanged, the formerly thoracic neural crest gives rise to cholinergic neurons of the parasympathetic ganglia and the formerly vagal neural crest gives rise to adrenergic neurons in the sympathetic ganglia.64 In both situations the exchange of trunk-level neural tube segments from one axial position to another resulted in neural crest that migrated, differentiated and contributed to tissues appropriate for their new location rather than their origin. It is interesting to note however that both vagal and thoracic presumptive neural crest cells express the enzymes for synthesizing both acetylcholine and norepinephrine and yet during normal embryonic development this dual potential is never realized by either the vagal or thoracic neural crest. Therefore this implies that the differentiation of a neural crest cell depends largely on its local environment and that neural crest cells may typically have a broader differentiation capacity than is usually realized.65

Neural crest cell ablation experiments provided further evidence that properties of neural crest cell identity are not imprinted before migration. Small regions of midbrain, occipital and cervical neural crest cells can be surgically ablated without significantly compromising development of the neck and face.66-68 The absence of major craniofacial abnormalities in these instances was due to the regeneration of neural crest cells which in-filled and produced the tissues that would have otherwise been formed by the ablated cells. This again demonstrates the regulative nature of embryonic development and the plasticity and adaptability of the neural crest cell population as a whole.

While neural crest cells from each axial level can form neurons, glia and melanocytes, a significant difference exists between cranial and trunk neural crest cells with respect to their endogenous ability to generate skeletal derivatives such as bone and cartilage. These hard tissue derivatives are typical of cranial neural crest cells while, in contrast, trunk neural crest cells are thought to generally lack skeletogenic potential. However this idea was recently overturned via both in vitro and in vivo analyses.69 By exploiting culture media typically used for growing bone and cartilage cells, trunk neural crest cells were demonstrated to have the ability to generate these hard cell and tissue types in vitro. Furthermore, this study also revealed that if the same trunk neural crest cells are placed directly into developing facial structures, these cells will contribute to cranial skeletal elements in vivo.

The ability of trunk neural crest to form skeletal elements is consistent with earlier demonstrations that rostral trunk neural crest cells could contribute to tooth formation when challenged with mandibular epithelium.70,71 Interestingly, despite the skeletogenic potential of trunk neural crest cells not being realized during normal amniote development, fossil fish display extensive caudo-cranial exoskeletal coverings of dermal bone and dentine, tissues that are typical neural crest cell derivatives.69 This suggests that although neural crest cells from each axial level may have a similar intrinsic potential, the ability to generate the wide repertoire of possible derivatives is controlled through extrinsic environmental factors in the embryo and as such plasticity may be an inherent property of neural crest cells.

Plasticity in Neural Crest Cell Migration

Numerous experiments have also shown that premigratory neural crest cells are not irreversibly programmed with respect to their routes of migration. Neural crest cells that are anteriorly or posteriorly transplanted to different positions along the neural tube, do not, for the most part, seek out their original path or final targets but rather migrate along pathways that are typically appropriate of their new location.55,64,72 Recent investigations emphasize the importance of the microenvironment adjacent to the neural tube in regulating the pathways of neural crest cell migration.54,63,73,74

The influence of the microenvironment is clearly evident from lineage tracing and time-lapse imaging of neural crest cell migration in avian embryos. Rhombomeres 3 and 5 of the hindbrain generate small numbers of neural crest cells, but rather than migrating laterally like neural crest cells derived from the rest of the hindbrain, odd rhombomere derived neural crest cells migrate anteriorly and posteriorly to join the segregated neural crest streams. On occasions when a rhombomere 3 derived neural crest cell does delaminate and migrate laterally, its filopodia collapse as it contacts the mesenchymal environment adjacent to rhombomere 3.75 These results underscore the importance of the environment adjacent to the neural tube in regulating the pathways of neural crest cell migration. Furthermore they demonstrate that the presence of neural crest free zones and the segregation of neural crest cells into discrete streams is not an intrinsic property of the vertebrate hindbrain or the neural crest cells.

Importantly, the mechanism of regulation of neural crest migration pathways by the adjacent environment may be conserved between mouse and chick. In ErbB4 null mutant mice neural crest cells from rhombomere 4 acquire the ability to migrate through the dorsal mesenchyme adjacent to rhombomere 3, which is normally free of neural crest cells.74 The aberrant migration arises as a consequence of changes in the paraxial mesenchyme environment and is not autonomous to the neural crest cells. Since ErbB4 is normally expressed in rhombomeres 3 and 5 this phenotype reflects defects in signalling between the hindbrain and the adjacent environment branchial arches in mutant embryos. To date few molecules that influence the path finding of cranial neural crest cells have been identified, however evidence obtained primarily from analyses in frog embryos suggests that bi-directional Eph/ephrin cell signalling plays an important role in keeping the neural crest cell streams segregated ventrally.76

Although overall the migratory patterns of broad regions of the neural crest appear to be extrinsically regulated and generally conserved between species, specific patterns within these populations emerge which may be exceptions to the general rule. In the trunk, neural crest cells traverse two distinct migration pathways.77,78 Initially trunk neural crest cells migrate ventrally between the somites and the neural tube. Some of these cells continue migrating ventrally until they reach the dorsal aorta whereas a subpopulation migrates laterally along the basal surface of the myotome, penetrating only the anterior half of each somite. This patterned migration through the somites is critical for establishing the segmental layout of the adult peripheral nervous system. Approximately one day after the ventrally migrating neural crest cells emigrate, trunk neural crest cells also begin to migrate dorsolaterally between the ectoderm and somites. The sub-ectodermally migrating neural crest cells are destined to become pigment cells. This melanoblast neural crest cell lineage is the only neural crest cell population capable of following the dorsolateral route at the trunk level. When early emigrating nonmelanogenic neural crest cells are transplanted into the neural tube of avian embryos at a time and place where both migratory pathways are accessible, the transplanted cells migrate only along the ventral pathway.79 This suggests that in the trunk, to migrate along the dorsolateral pathway, a neural crest cell must have already committed to the melanocyte lineage. While this first, and to date only, evidence that cell autonomous characteristics dictates neural crest migratory properties, it is unlikely to remain the only example.

These studies highlight the complexity in regulating neural crest cell patterning and the balance between signals acquired in the neuroepithelium during formation versus signals received from the extrinsic tissue environments during migration. This intricate regulation affects not only the migratory properties of neural crest cells but also dramatically influences their differentiation.

Neural Crest Cells Direct Species-Specific Craniofacial Morphology

The ability of neural crest cells to influence species-specific facial structure was first illustrated by classical experiments in which neural tube segments were transplanted between frog and salamanders.80-83 More recently, interspecies transplants in avians have been used to further elucidate the role of neural crest in patterning face morphology.84,85 For example, the beaks of ducks and quails are distinct in shape. The duck has a long relatively flat bill, whereas quails possess a shorter and more pointed beak. Despite similar coordinated differentiation of multiple tissue types, beak morphogenesis can be distinguished in these two species by differences in timing of expression of key molecular markers during development. These differences have been utilized to demonstrate the ability of neural crest cells to direct the species-specific pattern facial morphogenesis.84 Analysis of reciprocal transplants of neural crest cells between duck and quail embryos revealed that transplanted donor neural crest cells direct the species-specific morphology of host beak formation. Transplantation of duck neural crest into quail embryos produced embryos with a duck-like beak and, conversely, transplantation of quail neural crest into duck embryo resulted in embryos that developed with a quail-like beak. More importantly however, analyses of molecular markers whose expression was temporally different between the two species demonstrated that the transplanted neural crest cells maintained their own species-specific temporal expression program and, moreover, imposed their species-specific temporal expression program on the adjacent host ectodermal tissue. This in turn led to alterations in the position and timing of differentiation of structures such as the egg tooth which is entirely derived from host tissue. The ability of transplanted neural crest to carry species-specific patterning information is also manifest in the morphology of the branchial cartilages, from which the mature beak and facial skeleton develop.85

These results demonstrate that at least one component of the original neural crest programming model holds true in that neural crest cells can directly influence the spatial patterns of cell differentiation around them. Given that the neural crest cells form most of the cartilage and bone that constitute the foundations or scaffolding in the head, it is not surprising that the progenitors of the framework directly impact formation of tissues and structures such as muscle fibers and the egg tooth which must be functionally integrated into the scaffold.

In theory one could interpret the results of interspecies transplants as evidence for autonomy or preprogramming of neural crest cell patterning in addition to the presentation of species specific characteristics. However, two things should be borne in mind when considering these studies. Firstly, large populations of neural crest cells were typically transplanted in these interspecies grafts. Secondly, the spatiotemporal patterns of morphogenesis signaling molecules and epithelial determinants that regulate branchial arch and craniofacial patterning are highly conserved between species. That the signals mediating interactions of craniofacial development are highly conserved is clearly evident in the dramatic example of ectopic tooth formation in the beaks of chickens. Teeth have been missing in birds for 60 million years or more.86 In toothed vertebrates, teeth develop from a combination of oral ectoderm and neural crest-derived mesenchyme. In mouse, the source of instructive signals that initiate tooth development is the oral epithelium, which induces tooth formation in neural crest-derived mesenchyme.71,87 In vitro coculture assays between chick oral epithelium and mouse neural crest-derived tooth mesenchyme suggest that chick epithelium retains its capacity to induce tooth formation, whereas the avian neural crest has lost the ability to respond to the inductive signals.88-90 Tellingly, when tooth-forming mouse cranial neural crest is transplanted into chick, evidence of tooth-like structures were observed.91 Thus, the chick epithelium retains the ability to instruct neural crest to form teeth and the cranial neural crest of mouse is capable of interpreting those signals from the chick epithelium. The donor cells still undergo their typical differentiation program due to the highly conserved nature of branchial arch patterning between these species. These results should not be taken as evidence of neural crest cell preprogramming or autonomy because recombination of the same population of first branchial arch neural crest cells with second branchial arch epithelium from mice does not result in tooth differentiation.70 The spatiotemporal cascade of signaling molecules and determinants is more highly conserved for the first branchial arch between species than it is for the first and second branchial arches within a species. Ectopic tooth formation in chick branchial arches thus demonstrates the influence of neural crest cells on craniofacial patterning but also the complexity of the tissue interactions that regulate head and facial morphogenesis.

Patterning of the Head and Face by Non-Neural Crest Tissues

While the importance of neural crest cells to craniofacial development is clear, it is also true that neural crest is not the only tissue that plays a role in patterning early morphogenesis of the head. Some aspects of facial patterning require no contribution from neural crest. Ablation of neural crest destined for the second and third branchial arches in chick embryos does not compromise early development or regional specification of those arches nor the formation of epibranchial placodes.92 Formation of the epibranchial neurogenic placodes is induced by signals from the pharyngeal endoderm and does not require a contribution from the neural crest.93 Similarly, Hoxa1/Hoxb1 double null mutant mice that lack specifically second branchial arch neural crest develop second arches in which early patterning is relatively normal.94 Although the skeletal derivatives fail to form since they are derived from neural crest cells which are missing in these instances, these studies demonstrate that early branchial arch formation and patterning can be initiated appropriately, independent of any contribution from migratory neural crest cells.

In contrast, many aspects of craniofacial patterning require cross-talk between neural crest and non-neural crest tissues. For example, epithelial-mesenchymal interactions between the epithelia of the frontonasal and mesenchymal neural crest regulate outgrowth of the facial primordial.95 Tooth formation also involves epithelial-mesenchymal interactions between the oral ectoderm and mesenchymal neural crest (for review see ref. 96). The endoderm of the foregut has the ability to instruct neural crest cells with respect to orientation, shape, size and position of the facial skeletal elements.43 Other endodermal tissues also influence neural crest patterning. In zebrafish, endoderm is required for survival and differentiation of the chondrogenic neural crest cells that give rise to the ventral head skeleton.97 Mesendodermal cells of the pharyngeal arches also play a role in patterning neural crest derived structures in zebrafish. Mutation of the tbx1 gene, which acts cell autonomously in that tissue, disrupts development of the neural crest-derived pharyngeal arch cartilages and associated structures.98,99

Ectodermal tissues can also direct the patterning of neural crest within the developing head and face. Signals from neural epithelium and surface ectoderm direct the path finding of neural crest that stream from the hindbrain into the mesenchyme adjacent to rhombomeres 2, 4 and 6.100 Removal of the neuroepithelium and surface ectoderm overlying rhombomere 3 disrupts the normal segregation of the streams of neural crest and results in aberrant migration into the mesenchyme adjacent to rhombomere 3. An ectodermal region within the frontonasal process of a developing chick embryo functions as a signaling center directing outgrowth and patterning of the mandibular facial skeleton.101 When transplanted ectopically this frontonasal ectodermal zone causes duplications of neural crest-derived distal beak structures, the orientation of which is controlled by the position and orientation of the grafted tissue fragment.

Cranial mesoderm is also capable of influencing patterning of neural crest cells. When transplanted in isolation, mouse neural crest cells translocated from the second branchial arch level to the first branchial arch level exhibit plasticity, as shown by the down-regulation of a Hox reporter transgene. However, if mesodermal cells from the second branchial arch are included with the transplanted neural crest, expression of the Hox transgene is maintained.54 Thus, signals from the cranial mesoderm are important for regulating the identity of the second branchial arch neural crest cells.

Molecular Pathways Involved in Neural Crest Signaling

In molecular terms, interactions between neural crest cells and other tissues is likely to involve many of the same signaling molecules that are known to regulate the patterning of neural tube and limb buds. These include retinoic acid and members of the Sonic hedgehog (Shh), Bone morphogenic factor (BMP), and fibroblast growth factor (FGF) pathways.102-105

The Shh pathway is implicated in patterning head and face development by virtue of the dramatic human and murine craniofacial abnormalities that result from mutation of the Shh gene.106,107 In chick also, reduction or overexpression of SHH results in malformations of the frontonasal and maxillary processes.105,108 SHH also acts synergistically with FGF8 to promote outgrowth of neural crest-derived cartilage in the developing chick head.109

Several lines of evidence implicate the BMP pathway in regulating craniofacial patterning. Ectopic addition of retinoic acid and the BMP antagonist Noggin into developing chick maxilla causes repatterning of the frontonasal mass and results in duplication of neural crest-derived skeletal elements.110 Ectopic addition of BMP2 and BMP4 or reduction of BMP4 causes alterations in the development of the facial skeleton of chick.102,111 Recently, analysis of gene expression patterns in developing embryos of Darwin's finches has established a clear role for Bmp4 in craniofacial patterning.112 In this study, variation in Bmp4 expression correlated with naturally occurring differences in beak morphology between species of finch. Species with beaks shaped more broad and deep than long express Bmp4 earlier and at higher levels than species whose beak shape is relatively narrow and shallow. In addition, overexpression of Bmp4 in chick embryos altered beak morphogenesis and did so in a tissue-specific manner. Overexpression of Bmp4 in the facial ectoderm produced beaks that were smaller and narrower than normal and overexpression of Bmp4 in mesenchyme of the frontonasal process, much of which is neural crest-derived, resulted in beaks that were broader and deeper than normal. These results illustrate that beak morphogenesis is directed by BMP4 signaling via interactions of different tissue types.

FGFs are another family of signaling molecules that play an important role in patterning craniofacial skeletal development. Formation of the ventral head skeleton has been shown to require FGF3 signaling from the endoderm.97 In the developing embryo Fgf8 is expressed in the isthmus at the midbrain-hindbrain junction and also in the telencephalon and in the branchial arch ectoderm. Rostral-caudal polarity of the first branchial arch is determined by an FGF8 signal from the rostral epithelium.113 Reduction of Fgf8 expression in the forebrain disrupts structures such as the upper beak and deletion or overexpression of Fgf8 in the branchial arches disrupts the patterning of the arches.105,114-116

Reciprocal Interactions

Many of the organs and tissues to which the neural crest contributes are composed of multiple tissues types whose intimate interconnection is essential for function. For example, a bird beak requires contributions from multiple germ layers. The cartilage and connective tissues are derived from neural crest, the outer cornified layer comes from facial ectoderm, blood vessels and muscles are produced by mesoderm and the oral cavity is lined by endodermal cells.1,7,117 In addition to their juxtaposition with other cell types at their site of differentiation, neural crest cells are also exposed to a variety of different tissue environments as they migrate along their route from the neural tube to their final destination (Fig. 2). Clearly these associations of neural crest with other cells types offer abundant opportunities for interactions and cross-signaling between neural crest and other tissues.

Figure 2. Migratory neural crest cells contact multiple tissue types during craniofacial morphogenesis.

Figure 2

Migratory neural crest cells contact multiple tissue types during craniofacial morphogenesis. A) Neural crest cells emigrating from the closing cranial neural folds of a mouse embryo at 9.0 days of development are revealed by GFP expressed from the Pax3 (more...)

Regulation of craniofacial patterning by reciprocal inductions between neural crest and other tissues is clearly demonstrated by a recent study of FGF8 signaling in frontonasal process and branchial arch development. In this example the Hox-negative anterior neural crest were found to influence the expression of Fgf8 in other cell types and in turn, the neural crest were influenced by FGF8 signaling emanating from the non-neural crest tissue.118 FGF8 activity in branchial arch ectoderm and the telencephalon was shown to require the presence of Hox-negative neural crest as ablation of the Hox-negative neural crest resulted in loss of Fgf8 expression in the arch and neural tissue. Exogenous addition of FGF8 to the surface ectoderm of presumptive first branchial arch largely rescued formation of the facial skeleton in embryos from which the Hox-negative neural crest had been ablated. These results demonstrate that anterior neural crest induces FGF8 activity in the ectodermal and epithelial tissues of the branchial arch ectoderm and telencephalon, and subsequently that FGF8 signaling from these tissues signals the maintenance and survival of the neural crest cells.


Patterning and morphogenesis of neural crest-derived tissues within a developing vertebrate embryo are regulated by reciprocal interactions between neural crest and other tissue types. These cellular interactions involve signals and organizing centers mediated by the same key molecular families that regulate other aspects of patterning and morphogenesis within a developing embryo, namely the BMP, SHH and FGF pathways. Axial identity of neural crest is controlled by a combinatorial pattern of Hox gene expression, which is regulated independently within the hindbrain and migratory neural crest. The developmental program that regulates neural crest cell fate is plastic in the sense that the neural crest cells are influenced by signals from each other as well as tissues in their migratory environment. At the same time, neural crest cells are capable of directing patterning and morphogenesis within a developing embryo, controlling the formation of structures composed of multiple tissue types. The distinction between plasticity and maintenance of identity is a matter of scale. As a cohort of interacting cells, neural crest cells carry information that directs the axial pattern and species-specific morphology of the head and face. As individual cells, neural crest cells are responsive to signals from each other as well as from non-neural crest tissues in the environment.

Neural crest cell patterning therefore relies on a complex balance between signals acquired in the neuroepithelium during their formation together with the signals from the tissues that the neural crest cells contact and interact with during their migration. The studies described in this review clearly highlight the difficulty in trying to condense the complexity of neural crest cell patterning into simple general models. There will always be species specific, region specific or context dependent exceptions to the general rules and models hypothesized. As much as these general fundamental mechanisms have been important for the conservation of basic patterning it is important to note that the exceptions to the rules are intricately connected to evolutionary diversity and should also be embraced.

Craniofacial development is a complex 3-dimensional morphogenetic process and most craniofacial abnormalities arise through defects in neural crest cell formation, migration and differentiation. However, the analyses described in this review clearly demonstrate that the cause of craniofacial anomalies are not limited to defects intrinsic to the neural crest cells but may sometimes result from a primary defect in the ectoderm, endoderm or mesoderm tissues with which the neural crest cells interact. The key to furthering our understanding of congenital craniofacial abnormalities is a better characterization of the molecular determinants of the endoderm, ectoderm and mesoderm and the effects that these molecules have on neural crest cell development. Elucidating these interactions will also enhance our appreciation of the basis of neural crest cell and craniofacial evolution and diversity.


We thank Robb Krumlauf for the original scanning electron micrograph and Natalie Jones for in situ hybridization and skeletal figures. This work is supported by research funds from the Stowers Institute, a Basil O'Connor Research Scholar Award (#5-FY03-16) from the March of Dimes and grant RO1 DE 016082-01 from the National Institute of Dental and Craniofacial Research to PT.


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