3 Derivatives Of Neural Crest Cells, Neural Crest, Neural Crest


Neural crest cells (NCCs) comprise a multipotent, migratory cell population that generates a diverse array of cell and tissue types during vertebrate development. These include cartilage and bone, tendons, and connective tissue, as well as neurons, glia, melanocytes, and endocrine and adipose cells; this remarkable lineage potential persists into adult life. Taken together with a limited capacity for self-renewal, neural crest cells bear the hallmarks of stem and progenitor cells and are considered to be synonymous with vertebrate evolution. The neural crest has provided a system for exploring the mechanisms that govern developmental processes such as morphogenetic induction, cell migration, and fate determination. Today, much of the focus on neural crest cells revolves around their stem cell-like characteristics and potential for use in regenerative medicine. A thorough understanding of the signals and switches that govern mammalian neural crest patterning is central to potential therapeutic application of these cells and better appreciation of the role that neural crest cells play in vertebrate evolution, development, and disease.

Đang xem: 3 derivatives of neural crest cells


At the end of gastrulation, after generation of the three primary germ layers is complete, the ectoderm is subdivided into two distinct domains: the non-neural or surface ectoderm and the neural ectoderm. The surface ectoderm will eventually form placodes, skin, and dermis, whereas the neural ectoderm will ultimately give rise to the central nervous system. The neural ectoderm (also known as the neuroepithelium or neural plate) extends almost the entire length of the vertebrate axis, and during neurulation, the left and right halves elevate and fuse to form a neural tube. It is during this neurulation process that neural crest cells (NCCs) are formed within the dorsal-most part of the neuroepithelium at the junction with the surface ectoderm, a region termed the “neural plate border.” Explants of neural plate cultured in vitro do not endogenously generate neural crest cells. Thus, neural crest cell induction has been viewed as a multistep process, requiring an inducer (i.e., the ectoderm or paraxial mesoderm) and a competent receiving tissue (i.e., the neural plate). Furthermore, these interactions between non-neural and neural tissues are contact-mediated, suggesting that inductive signals pass to the neuroepithelium to induce neural crest cell formation (Selleck and Bronner-Fraser 1995).

Initially, neural crest cells are integrated within the neuroepithelium and are morphologically indistinguishable from the other neuroepithelial cells. However, in response to contact-mediated inductive signals from the surface ectoderm and underlying mesoderm, neural crest cells are born and undergo an epithelial-to-mesenchymal transition, after which they delaminate from the neuroepithelium. Some neural crest cells may also be derived from the surface ectoderm. Neural crest cells then migrate extensively to several different locations in the embryo (Fig. 1). Although the bone morphogenetic protein (BMP), fibroblast growth factor (FGF), and Wnt signaling families have each been identified as key signaling regulators of neural crest cell formation in diverse species such as avians, fish, and amphibians, there is no conclusive evidence that supports an absolute role for these same factors in mammalian neural crest cell induction (Crane and Trainor 2006). These signaling pathways appear to be more important for specifying cell-type differentiation within the mammalian neural crest cell lineage. Therefore, the signals and switches governing mammalian neural crest cell formation remain to be identified.


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Figure 1.

Cranial neural crest cell migration and differentiation. (A) Schematic representation of the pathways of mammalian cranial neural crest cell migration and the respective expression and interaction of Sox10, FoxD3, FGF, and Dlx signals and switches that govern neural crest cell differentiation. (B) Lateral, and (C) dorsal views of Alizarin Red- and Alcian Blue-stained bone and cartilage, respectively, in an embryonic day 18.5 (E18.5) mouse embryo.

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The delamination of neural crest cells from the neural tube requires significant cytoarchitectural and cell-adhesive changes and is typically recognized by the activity of members of the Snail transcription factor gene family. Snail1, for example, demarcates neural crest cells in mouse embryos (Sefton et al. 1998). Snail1 and Snail2 can directly repress the cell adhesion molecule E-cadherin by binding to its promoter, which is thought to facilitate cell migration (Cano et al. 2000; Bolos et al. 2003). However, in contrast to avians, fish, and amphibians, a requirement for the Snail genes in mammalian neural crest cell induction is conspicuously absent. Conditional loss-of-function analyses of Snail1 and Snail2 either individually or in combination do not inhibit neural crest cell induction and delamination in mice (Jiang et al. 1998; Murray and Gridley 2006). To date, only mutations in Zfhx1b, which is also known as Smad-interacting protein 1 (SIP1), have been shown to affect neural crest cell formation and delamination in mammalian embryos (Van de Putte et al. 2003). Zfhx1b knockout mice do not develop post-otic vagal neural crest cells, and the delamination of cranial neural crest cells is perturbed. This is due to the persistent expression of E-cadherin throughout the epidermis and neural tube. Hence, appropriate regulation of cell adhesion is critical for formation, epithelial-to-mesenchymal transition (EMT), and subsequent delamination and migration of mammalian neural crest cells.

During normal mammalian embryogenesis, neural crest cell induction and delamination begin at the level of the midbrain and continue as a wave that extends progressively caudal toward the tail. Thus, neural crest cells are born along nearly the entire length of the neuraxis and, based on their axial level of origin, can be classified into distinct axial groups: cranial, cardiac, vagal, trunk, and sacral, each of which shows specific migration pathways and differentiation capacities. The cranial neural crest gives rise to the majority of the bone and cartilage of the head and face, as well as to nerve ganglia, smooth muscle, connective tissue, and pigment cells (Fig. 1A). The cardiac neural crest contributes to heart development by forming the aorticopulmonary septum and conotruncal cushions, whereas the vagal and sacral neural crest gives rise to enteric ganglia of the gut. Finally, the trunk neural crest give rise to neurons and glia that contribute to the peripheral nervous system, to secretory cells of the endocrine system, and to pigment cells of the skin. The remarkable capacity of neuroectoderm-derived neural crest cells to differentiate into both neuronal and mesenchymal derivatives has led to the neural crest being described as the fourth germ layer (Hall 1999). There are a couple of possible mechanisms that can account for the ability of neural crest cells to differentiate into such diverse cell types and tissues. Neural crest cells could comprise a heterogeneous mixture of progenitor cells, with each progenitor giving rise to a distinct cell type within the body. This would require some degree of neural crest cell specification before their emigration from neural tube and be largely dependent on intrinsic signals regulating their development. Alternatively, neural crest cells could be multipotent, with their differentiation into multiple distinct cell types being dependent on extrinsic signals emanating from the tissues with which they contact during their migration. The question of extrinsic versus intrinsic specification of neural crest cells and the appropriateness of their classification as true stem cells or progenitor cells has been addressed extensively elsewhere (Trainor and Krumlauf 2001; Trainor 2003; Trainor et al. 2003; Crane and Trainor 2006). Suffice it to say that differing opinions are attributable to semantic arguments and the context-dependent nature of specific experiments. Neural crest cells show some of the key hallmarks of stem and progenitor cells, and their development is governed by a balance between intrinsic and extrinsic signals; however, neural crest cells are only generated transiently during embryogenesis. Neural crest cell differentiation has thus proven to be a significant model for understanding cell signaling and remains relevant because of the importance of neural crest cells in vertebrate development, evolution, and disease. Therefore, in this article, we discuss the signals and switches that regulate mammalian neural crest cell differentiation with a particular emphasis on skeletogenic and neuronal specification, the primary derivatives of the head and trunk, respectively.

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The craniofacial complex is anatomically the most sophisticated structure of the vertebrate body. Composed of a neurocranium (brain case) and viscerocranium (components derived from the pharyngeal arches), the cranioskeletal complex houses and protects the brain as well as the majority of the sense organs (Fig. 1B,C). It is important to note that the craniofacial skeleton across all craniates is of dual origin, being derived from both neural crest cells and mesodermal cells; however, the majority of the bone, cartilage, and connective tissue is derived from the neural crest (Jiang et al. 2002; Yoshida et al. 2008). In the mammalian neurocranium, for example, the meninges and frontal bones are derived from neural crest cells as is the suture mesenchyme, whereas the parietal bone is mesoderm-derived (Jiang et al. 2002). Two types of bone formation occur in the head. Intramembranous bone formation occurs by the direct differentiation of mesenchymal condensations into osteoblasts that lay down a mineralized matrix. In contrast, in endochondral bone formation, chondrocytes derived from mesenchymal condensations produce a cartilaginous framework that subsequently becomes hypertrophic and is replaced by osteoblasts and bone matrix.

2.1 Hox-Positive versus Non-Hox-Negative Activity in Cranial Neural Crest Cells

Cranial neural crest cells in mouse embryos migrate in stereotypical patterns that are highly conserved across vertebrates (Kulesa et al. 2004) and use a complex array of intrinsic and extrinsic signaling cues (Trainor 2005). For craniofacial skeletogenesis, following colonization of the facial prominences and branchial arches, neural crest cells aggregate, condense, and differentiate from a common osteochondral progenitor toward more specific chondrogenic or osteogenic cell fates in response to signals from the surrounding epithelia, which include the neuroepithelium, endoderm, ectoderm, and mesoderm (Hall 1999; Trainor and Krumlauf 2001).

Neural crest cells have unique transcriptional identities correlating with their anterior–posterior axial origin within the neural plate. Most importantly, the cranial neural crest cells are subdivided into Hox-gene-negative- versus Hox-gene-positive-expressing cells. The first pharyngeal arch and more rostral populations of neural crest cells do not express Hox genes. Hox gene expression is associated with second and more caudal pharyngeal arch populations of neural crest cells. In mice, neural crest cells that colonize the first arch form skeletal tissue such as Meckel’s cartilage, the maxillae, and the dentary bones, whereas neural crest cells of the second arch form Reichert’s cartilage. The proximal region of Meckel’s cartilage develops into two of the middle ear bones, the malleus, and the incus, whereas Reichert’s cartilage forms the stapes (third bone of the middle ear), the styloid process of the temporal bone, the lesser horn, and part of the hyoid bone. Both endochondral and intramembranous ossification occurs during first pharyngeal arch differentiation, in contrast to primarily endochondral ossification in the second pharyngeal arch.

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In mice, targeted inactivation of Hoxa2 results in lethality at birth and homeotic transformations of second arch neural crest-derived elements into proximal first arch derivatives, including a partial duplication of Meckel’s cartilage and ossification centers of the middle ear bones (Rijli et al. 1993). In these mutants, ectopic intramembranous ossification takes place in the second arch, resulting in duplicated jaw structures. Therefore, Hoxa2 is essential for proper patterning of neural crest cell differentiation and, in fact, functions as an inhibitor of intramembranous and endochondral ossification (Rijli et al. 1993; Kanzler et al. 1998). Consistent with this, overexpression of Hoxa2 in the first branchial arch of avian (Grammatopoulos et al. 2000) and frog (Pasqualetti et al. 2000) embryos suppresses jaw formation. Inroads have been made into the mechanisms by which Hoxa2 specifically influences cranial neural crest cell differentiation (Kanzler et al. 1998). During normal development, Hoxa2 is widely expressed in the second arch mesenchyme but is excluded from the chondrogenic condensations in the core of the arches. In the absence of Hoxa2, ectopic chondrogenesis coincides with an expansion of Sox9 expression into the normal Hoxa2 expression domain, where it is not normally expressed. Sox9 is a direct regulator of the cartilage-specific gene Col2a1 (Bell et al. 1997; Ng et al. 1997), and, using a mouse transgenic approach, it has been shown that changes in Sox9 expression are indeed responsible for the ectopic elements found in the second arch of Hoxa2 mutants. This is also supported by misexpression of Sox9 in the second arch, which produces a phenotype resembling that of the Hoxa2 mutants. Therefore, Hoxa2 acts very early in the chondrogenic pathway upstream of Sox9 during neural crest cell differentiation. In addition, Runx2 is up-regulated in the second branchial arch of Hoxa2 mutant embryos. Runx2 is required for bone formation, suggesting that the inhibition of Runx2 activity might mediate Hoxa2 suppression of intramembranous and endochondral bone formation.

Hox gene expression in cranial neural crest cells is considered to be inhibitory to skeletogenic differentiation and, in particular, incompatible with jaw formation (Trainor and Krumlauf 2001). Thus, the lack of expression of Hox genes in ectomesenchymal cells is imperative for proper patterning and skeletal development of the vertebrate face (Couly et al. 2002). Furthermore, the simultaneous inactivation of all Hoxa cluster genes leads to multiple jaw and first arch structures, partially replacing second, third, and fourth arch derivatives (Minoux et al. 2009). This pattern of Hox and non-Hox gene expression in cranial neural crest cells is conserved across vertebrate gnathostomes, and, interestingly, the vertebrate agnathan Lampetra fluviatilis shows expression of Hox6 in the first branchial arch (Cohn 2002), which may help to explain the absence of jaw formation in lampreys despite the presence of neural crest cells. Thus, jaw evolution may have coincided with suppression of Hox gene expression in the first branchial arch (Trainor 2003; Trainor et al. 2003). However, the presence or absence of Hox gene expression in the first branchial arch is likely too simplistic a model for jaw skeletal potency because another species of lamprey, Lethenteron japonicum, appears to maintain a Hox-expression-free mandible (Takio et al. 2004).

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