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Oral Pathology

Author: Dr. Manjul Tiwari.

The, evolution of the head is considered fundamental to the origins of vertebrates. The vertebrate head is a complex assemblage of cranial specializations, including the central and peripheral nervous systems, viscero- and neurocranium, musculature and connective tissue. The development of these structures depends on signaling interactions between the stomodeal ectoderm and underlying neural crest cells of that region. The facial defects mainly depend upon migration, differentiation of neural crest cell. This review of paper presents the migration, differentiation, induction of neural crest cell in craniofacial skeleton.

In 1868 a Swiss embryologist identified a band of cells sandwiched between the epidermal ectoderm and the neural tube in neurula stage chick embryos. These bands of cells which he called Zwischenstrang (the intermediate cord) were the source of cranial and spinal ganglia and today we know the intermediate cord as the neural crest. Although it was initially associated with the origins of neurons and ganglia, it has been from demonstrated in the 1890 s that the visceral cartilages of the head and dentine forming cells of the teeth in mud puppy Necturus will also arise from the neural crest.

The vertebrate neural crest is a pluripotent cell population derived from the lateral ridges of the neural plate during the early stages of the embryogenesis. Neural crest cells disperse from the dorsal surface of the neural tube and migrate extensively throughout the embryo, giving rise to the a wide variety of differentiated cell types. In the facial skeleton, cranial neural crest cells (CNCC) act as the fundamental building blocks for generating much of the skeleton and connective tissue of the head, in addition to the cranial ganglia peripheral nerves that innervate these skeletal structures. In the craniofacial region, the neural crest cells are the major source of the mesenchymal population that differentiates into osteoblasts, chondroblasts, and odontoblasts. One of the skeletal derivatives of the cranial neural crest is Meckel's cartilage. Initially, the mandibular skeleton consists only of Meckel's cartilage, which presumably functions developmentally as a skeletal element. However, it persists through out in bird life, but is rudimentary in mammals. A common finding in vertebrates is the highly organized and the reproducible migration of distinct CNCC streams, from their site of origin along the neural axis into the branchial arches. Manipulation of the CNCC primordial axial level in the chick neural tube by transplantation leads to crest migration and the generation of skeletal structures which commensurate with the original axial level of the transplant structures inappropriate for the new location. These findings led to the idea that CNCC were pre-patterned, replete with the necessary genetic information prior to their migration from the neural tube, allowing production of requisite skeletal structures in the correct position at their ultimate destination within the early cranium. Progressively more elegant and technically demanding transplantation and ablation experiments carried out in a variety of species have suggested a degree of plasticity in CNCC behavior. In particular, these cells appear to be influenced by local cell community effects and their very presence even dispensable for normal branchial arch patterning. This review presents the path of migration of neural crest cell in craniofacial skeleton, factors affecting and patterning of neural crest cell.

Induction and Migration of neural crest cells:
Neural crest cells arise uniformly at the dorso lateral edge of the closing neural folds, along almost the entire length of the vertebrate embryo neuraxis. This region corresponds to the interface between the non-neural ectoderm (presumptive epidermis or surface ectoderm) and the neural plate (neuroepithelium), a region commonly referred to as the neural plate border.
Neural crest cell induction requires contact mediated interactions between the surface ectoderm and neuroepithelium, each of these tissues contributes to the neural crest cell lineage. Lineage tracing studies have demonstrated that a single dorsal neural tube cell can give rise to both neural tube and neural crest derivatives. Thus it is logical to expect that bone morphogenetic proteins (BMPs), fibroblast growth factors (FGFs) and members of the WNT signalling family which are critical for specifying neural plate induction and determining the boundary of neural and epidermal fate, may also play important roles in inducing and specifying the differentiation of neural crest cells.
The migration and differentiation of neural crest cells is derived from experiments with avian neural crest cells. This is because the Quail cell nuclei have distinctive intrinsic characteristics that make them distinguishable from those of the chick; yet the quail cells apparently do not cause any alteration in the development of the chick.
Migrating neural crest cell are composed of the patterning genetic codes, this coded cell migrates gives as per the code and based on coding the path is divided in to two types which include cranial path and trunk path (vagal path ).
Cranial neural crest cells follow migratory routes that are unique to specific regions of the cephalic neural tube, that is, maxillary, zygomatic orbital palate with a stream of cells in an anterior-posterior wave in cranial region along with defined migratory pathway and are composed of specific codes. The migration of neural crest cells is presumably directed by factors within the resident tissues with which these migrating cells come in contact. While the neural crest migratory pathways have been extensively detailed, the factors that delineate these pathways are still under active investigation.

Factors mediating cell movement and neural crest differentiation:
Many control mechanisms have been implicated as important for determining the emigration movement, and direction of movement of the neural crest cells. The earliest known indicators of neural crest induction are Slug and Snail which normally act as transcriptional repressors. Snail binds to the promoter of the cell adhesion molecule E-cadherin, repressing its expression. Thus ectopic expression of Snail in epithelial cell lines results in the down regulation of E-cadherin, which represses epithelial to mesenchymal cell transformations and consequently inhibits cell migration. This implies that Snail may promote the epithelial to mesenchymal cell transitions associated with neural crest cell delamination and migration from the neural tube through effecting changes in cell adhesion. Slug antisense mRNA oligonucleotide treatment of Avian or Xenopus embryos results in the inhibition of cranial neural crest cell migration. BMP signaling has been shown to induce the expression of both Slug and cadherin6 demonstrating that the same signal can fulfill multiple roles during development. BMP signalling, which is critical for neural crest induction, also plays a role in neural crest delamination.
Certain evidence suggests that glycosaminoglycans are important in the migration of neural crest cells. The first environment encountered by the neural crest cells in avian embryos is acellular and rich in hyaluronate with a loose matrix of collagen. The presence of hyaluronate has been correlated with neural crest cell migration. The controversial role of hyaluronidase gives information regarding the migration of neural crest cells. It spreads out the collagen fibers in an extracellular space and increases the space within a tissue. However the chondroitin sulfate may act as a barrier to neural crest cell migration. The morphological observations suggest that, at least initially, the neural crest cells migrate along the basement membrane of the neural tube. Since neural crest cells lack the ability to penetrate the basement membrane, the basement membrane may dictate the direction of migration of the neural crest cells. Interaction of the neural crest cells with components of the basement membrane, such as laminin or fibronectin, may provide scaffolding along which the cells can migrate.
Neural crest cells express cell surface receptors for fibronectin and laminin and bind to both in vitro. Fibronectin plays crucial role not only in migration of neural crest cell to the destination also to the penetration in to the basement membrane. In experimental evidence it has been seen that addition of fibronectin speeds up the spread of neural crest cell and determine the actual pathways for neural crest cell migration. More recently noted factor which has a significant role in migration of neural crest cell is an extracellular glycoprotein seen along the migratory path.
This protein has been given numerous names including tenascin, cytotactin, glioma mesenchymal extracellular matrix protein, and J1 protein. The pattern of distribution of this protein along the neural crest migratory pathways suggests a role for tenascin in directing the migration of neural crest cells. In contrast to use of fibrnectin neural crest cell become spread out. However with the use of tenascin, neural crest cell become round and don't spread due to interference with integrin-mediated cell attachment to both fibronectin and laminin in primary chick fibroblast cells.
Previous in vitro studies have suggested that the formation of cartilage and bone from neural crest-derived ectomesenchyme is dependent upon prior interaction with embryonic epithelium. When this epithelium is enzymatically removed, the migrating neural crest cells do not into skeletal components. Epithelia from other embryonic sources can be substituted for the mandibular epithelium, but the substituting epithelium has inductive capabilities only during particular periods of embryogenesis, presumably during time periods when this epithelium has inductive capabilities for other systems. This reinforces the concept that the inductive agent for the formation of mandibular bone is dependent upon interaction with the mandibular epithelium. Tenascin/cytotactin is an extra- cellular protein that has been localized to the migratory pathway of the neural crest and has been shown to be associated with chondrogenic and osteogenic tissues undergoing differentiation. It is present in restricted distribution in tissues whose differentiative fate has been determined, but not yet expressed phenotypically. It apparently interacts with fibronectin, resulting in cell rounding and condensation.

One of the difficulties in studying neural crest cells in mammalian embryos has been the limited survival of rodents in whole-embryo cultures. The recent development of whole-embryo cultures provides a culture system that simplifies manipulation of early rodent embryos. In addition, chimeric recombination has not been possible in rodent embryos due to the unavailability of evolution intrinsically marked rodent cells. Upon availability of such cells and subsequent construction of chimeric recombinations, the actual and potential fates of the mammalian neural crest cells can be established. The availability of retrovirally marked cells and transgenic animals will further enhance our ability to trace the neural crest from their sites of origin to their sites of differentiation. A clearer picture of the developmental mechanisms involved in avian and mammalian craniofacial development should emerge in the near future.

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