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tHEORIES OF GROWTH

Presented by : Dr. Rajesh Gyawali Resident, Department of Orthodontics and Dentofacial Orthopaedics Faculty of Dentistry, Institute of Medicine, Kathmandu Guided by : Dr. Basant Kumar Shrestha Associate Prof. and Head Department of Orthodontics and Dentofacial Orthopaedics Faculty of Dentistry, Institute of Medicine, Kathmandu

Introduction Throughout its history, the field of orthodontics has adopted various treatment approaches. Despite their obvious differences, virtually all these orthodontic approaches share at least one fundamental characteristic: their rationale is based on opinions regarding the biological
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mechanisms of the development and growth of the craniofacial skeleton and dentition, and on the etiology and natural history of malocclusion and dentofacial abnormalities. By the end of the first half of the 20th century, the field of orthodontics in the United States was dominated by the theme stated initially by Angle and reiterated by Brodie that craniofacial growth could not be altered in any significant way. Thus, the primary role of the orthodontist was to treat a malocclusion by moving teeth into a more harmonious position relative to the facial type; facial growth could not be affected by orthodontic treatment. Theories of Growth Control It is a truism that growth is strongly influenced by genetic factors, but it also can be significantly affected by the environment in the form of nutritional status, degree of physical activity, health or illness, and a number of similar factors. Since a major part of the need for orthodontic treatment is created by disproportionate growth of the jaws, in order to understand the etiologic processes of malocclusion and dentofacial deformity, it is necessary to learn how facial growth is influenced and controlled. Great researches have been made in recent years in improving the understanding of growth control. But it is still unclear and intensive researches are being done in this field. 1. 2. 3. 4. 5. 6. 7. The major theories explaining growth are Genetic Theory Remodelling Theory Sutural Theory Cartilageneous Theory Functional matrix Theory Sevosystem Theory Van Limborghs Theory

Other theories related to craniofacial growth are 1. Enlows expanding V principle 2. Enlows counterpart principle 3. Neurotrophic process in oro-facial growth Genetic Theory The genetic theory simply said that genes determine all. This theory states that all growth is controlled by genetic influences and is pre programmed. Gene has a major role in establishing basic facial pattern and the features upon which internal and external "environment" then begins to play at some yet-to-be-understood levels. Although called a theory it was more assumed than proven. After the general assumptions were found to be flawed, some said "perhaps this part is genetically controlled while that is not," or "this part is more
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controlled by heredity than that." Such statements showed uneasiness with the all-embracing aspects of the' 'theory. " Remodeling Theory of Craniofacial Growth (1930) The research by Brash on bone provided the foundation for the development of the first general theory of craniofacial growththe remodeling theory. The principal tenets of the remodeling theory were that bone only grows appositionally at surfaces. growth of the jaws is characterized by deposition of bone at the posterior surfaces of the maxilla and mandible, sometimes described as Hunterian growth of the jaws. calvarial growth occurs via deposition of bone on the ectocranial surface of the cranial vault and resorption of bone endocranially.

Thus, the remodeling theory postulated that all of craniofacial skeletal growth occurs exclusively by bone remodelingselective addition and resorption of bone at its surfaces. Sutures and the cartilages of the craniofacial skeleton have little or no role in the growth of the craniofacial skeleton. The Sutural Theory (1940) The sutural theory was proposed by Weinmann and Sicher, two prominent anatomists. According to this theory, the connective tissue and cartilaginous joints of the craniofacial skeleton, much like epiphyses of long bones, are the principal locations at which intrinsic, genetically regulated, primary growth of bone takes place. Growth of the cranial vault is caused by the intrinsic pattern of expansive proliferative growth by sutural connective tissue that forces the bones of the vault away from each other; indicating the primacy of sutural growth for the determination of adult skull form Similarly, proliferation of sutural connective tissue in the circummaxillary suture system surrounding the maxillary skeletal complex forces the midface to grow downward and forward. The mandible was perceived as essentially a bent long bone, with the mandibular condyar cartilage being equivalent to the epiphyseal plates of long bones whose growth forces the mandible downward and forward, away from the cranial base.
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It is clear now that sutures are not primary determinants of craniofacial growth. Two lines of evidence lead to this conclusion. a. The first is that when an area of the suture between two facial bones is transplanted to another location (to a pouch in the abdomen, for instance), the tissue does not continue to grow. This indicates a lack of innate growth potential in the sutures. b. Second, it can be seen that growth at sutures will respond to outside influences under a number of circumstances. If cranial or facial bones are mechanically pulled apart at the sutures, new bone will fill in, and the bones will become larger than they would have been otherwise. If a suture is compressed, growth at that site will be impeded. Thus sutures must be considered areas that react-not primary determinants. Cartilageneous theory/ Nasal septum theory (1950) The Irish anatomist, James H. Scott, proposed an alternative explanation, the nasal septum theory, as the single and unified theory of craniofacial growth. According to the nasal septum theory, sutures play little or no direct role in the growth of the craniofacial skeleton. Rather, sutures are merely permissive, secondary, and compensatory sites of bone formation and growth. Primarily through comparative histological analysis, Scott concluded that the nasal septum is most active and important for craniofacial skeletal growth late prenatally and early postnatally, through approximately three to four years of age in humans. During that time, the anterior-inferior growth of the nasal septal cartilage, which is buttressed against the cranial base posteriorly, drives the midface downward and forward. The cranial base synchondroses, which are analogous to epiphyseal growth plates, were thought to have a longer lasting effect on craniofacial growth. Finally, Scott asserted that the cartilage of the mandibular condyles behaves similarly to cranial base and nasal septal cartilages, and directly determines the growth of the mandible as its pushes the mandible downward and forward.

Schematic representation of the nasal septum theory of craniofacial growth Growth of the nasal septal cartilage pushes the midface downward and forward relative to the anterior cranial base. This results in a separation of the midfacial suture system, which then fills in via secondary, compensatory sutural bone growth.

Two kinds of experiments have been carried out to test the idea that cartilage can serve as a true growth center. I. Analysis of the results of transplanting cartilage Transplantation experiments demonstrate that not all skeletal cartilage acts the same when transplanted. a. If a piece of the epiphyseal plate of a long bone is transplanted, it will continue to grow in a new location or in culture, indicating that these cartilages do have innate growth potential. b. Cartilage from the spheno-occipital synchondrosis of the cranial base also grows when transplanted, but not as well. It is difficult to obtain cartilage from the cranial base to transplant, particularly at an early age, when the cartilage is actively growing under normal conditions; perhaps this explains why it does not grow in vitro as much as epiphyseal plate cartilage. c. Cartilage from the nasal septum gave equivocal results: sometimes it grew, sometimes it did not. In more precise recent experiments, however, nasal septal cartilage was found to grow nearly as well in culture as epiphyseal plate cartilage. d. Little or no growth was observed when the mandibular condyle was transplanted, and cartilage from the mandibular condyle showed significantly less growth in culture than the other cartilages. From these experiments, the other cartilages appear capable of acting as growth centers, but the mandibular condylar cartilage does not. I. Evaluation of the effect of growth on removing cartilage at early age. Removing a cartilaginous area stops or diminishes growth, if it really was an important center for growth. In rodents, removing a segment of the cartilaginous nasal septum causes a considerable deficit in growth of the midface. It does not necessarily follow, however, that the entire effect on growth in such experiments results from loss of the cartilage. It can be argued that the surgery
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itself and the accompanying interference with blood supply to the area, not the loss of the cartilage, cause the growth changes. There are few reported cases of early loss of the cartilaginous nasal septum in humans. One individual in whom the entire septum was removed at age 8 after an injury there is midface deficiency developed, but one cannot confidently attribute this to the loss of the cartilage. Nevertheless, the loss of growth in experimental animals when this cartilage is removed is great enough to lead most observers to conclude that the septal cartilage does have some innate growth potential, whose loss makes a difference in maxillary growth, and the rare human cases support this view. Paradigm Shift in Craniofacial Biology (1960-1980) Kuhn defines "normal science" as the research findings generally agreed to be basic to a scientific field. Kuhn invents a new term (by distorting the meaning of a classic Greek word)-"paradigm"-by which he means the current conceptual framework of a scientific field. Kuhn's "paradigm" is closely related to his ideas of "normal science," but paradigms change, new paradigms are suggested, and paradigms may be out of step with the normal science of the time. The result is conflict within a field-Kuhn's "scientific revolution." Gradually, a new paradigm assumes dominance, and a new normal science for the field emerges. For some time there have been attempts to provide an overriding conceptual framework for all craniofacial growth or, failing that, a neat synthesis of several "theories." These efforts have generally not yet been successful because of the varied aspects and complicated nature of craniofacial growth. It is, however, useful for us to review the evolution of the governing concepts in the field of facial growth through the years. Kuhn and Carlson would call these "paradigms."

Normal Science Scientific Revolution Normal Science The major emphasis of research in craniofacial biology and its clinical application in orthodontics, especially in the United States, during the 1950s and 1960s was on the specific location(s) of the center(s) at which the inherited traits determining craniofacial growth and form were actually expressed.
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Areas of the skeleton that exhibit independent growth are referred to as growth centers. Locations at which active skeletal growth occurs as a secondary, compensatory effect were defined as growth sites. Growth sites lack direct genetic influence and are influenced by other factors, such as the remote primary growth centers and the environment. Sutures and periosteum were noted as clear and definitive examples of adaptive growth sites. Although this terminology did help to clarify some issues surrounding craniofacial growth research, it did little to resolve the issue of the degree to which and how growth and form of the craniofacial skeleton were determined via heredity. Attention thus focused on the locations within the craniofacial skeleton where the presumptive forces of heredity were activesuch as at bone surfaces, sutures, cranial base synchondroses, and the mandibular condyles. The issue was not whether the growth and form of the craniofacial skeleton was inherited through the action of genes, but where is this complex pattern of heredity expressed. An alternative approach to the presumption of genetic predetermination of craniofacial growth had a long history in Europe. It was Melvin Moss, who published in the American Journal of Physical Anthropology on functional craniology. Moss then extended these concepts to clinical orthodontics as a new theory of craniofacial growth, the functional matrix hypothesis. These two papers were historic, benchmark events for all of craniofacial biology and clinical orthodontics as they established dialectic not between competing theories, but between competing paradigms of craniofacial growth. Introduced in the early 1960s, at a time when emphasis was on the relative immutability of craniofacial growth and the location of growth centers within the craniofacial skeleton, Moss viewpoint was not merely debatable, it was against the existing belief. The functional matrix hypothesis was a principal catalyst of a new way of looking at craniofacial growth, which became known as the functional paradigm. Whereas the genomic paradigm viewed craniofacial growth as primarily genetically predetermined and immutable, the functional paradigm emphasized the plasticity of development and growth of the craniofacial skeleton. Emphasis was placed on understanding the epigenetic interaction of intrinsic and extrinsic factors that result in variations in craniofacial form and on the potential of modification of craniofacial growth and form using the principals of orthodontics and dentofacial orthopedics. The historically older genomic paradigm emphasized the relative immutability of craniofacial growth and form; orthodontic treatment focused on tooth movement to correct malocclusion and to compensate for discrepancies within the maxillomandibular skeleton. The principles of
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the functional paradigm supported consideration of the use of dentofacial orthopedic techniques to correct a developing malocclusion or facial deformity. Functional Matrix Hypothesis (1960) The functional matrix hypothesis of Moss is defined as the origin, form, position, growth and maintenance of all the skeletal tissues and organs are always secondary, compensatory and necessary responses to chronologically and morphologically prior events or processes that occur in specifically related non skeletal tissues, organs or functioning spaces. The basic views of the functional matrix hypothesis are simple. Fundamentally, the functional matrix hypothesis maintains that, heredity and the genes play no significant deterministic role in the growth of skeletal structures in general and of the craniofacial skeleton in particular. The craniofacial skeleton, like all skeletal structures throughout the body, develops initially and grows in direct response to its extrinsic, epigenetic environment. As stated by Moss, bones do not grow; bones are grown. A number of relatively independent functions are carried out in the craniofacial region of the human body like respiration, mastication, swallowing, speech etc. Each of these functions is carried out by functional cranial component. Each functional cranial component consists of all the tissues, organs, spaces and skeletal parts necessary to carry out the given functions. Functional cranial components are comprised of the following two elements: (1) a functional matrix and (2) a skeletal unit. The functional matrix refers to all the soft tissues and spaces that perform a given function. The skeletal unit refers to the bony structures that support the functional matrix and thus are necessary or permissive for that function. Individual bones defined according to traditional anatomy may be comprised of a number of overlapping skeletal units as the skeletal unit refers not to the individual bone directly, but to the function(s) that it supports. There are two types of functional matrices The periosteal matrix corresponds to the immediate local environment, typically muscles, blood vessels, and nerves. The capsular matrix is defined as the organs and spaces that occupy a broader anatomical complex.

Within the craniofacial complex, the capsular matrices would include such organs as the brain and globes of the eyes, as well as actual spaces such as the nasopharynx and oropharynx.
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There are also two categories of skeletal units: (1) microskeletal units and (2) macroskeletal units. Functional variations in the periosteal matrix, such as muscle activity for example, may be locally expressed within the microskeletal unit as tuberosities and processes or ridges for muscle attachment. Growth in size and shape of microskeletal units is typically associated with transformation from an embryonic cell type to an osteoblast-osteocyte associated with periosteal deposition. Changes in the size and shape of macroskeletal units, which include the neurocranium and maxillomandibular complex, are the result primarily of expansion of the capsular matrices and translational growth of associated skeletal structures. According to the functional matrix hypothesis, the craniofacial skeleton does not grow in primary fashion to permit expansion of the soft tissues, organs and spaces comprising the functional matrix. Rather, translation of skeletal units and associated local transformational bone growth of bone tissue occurs secondarily and in compensatory fashion to growth of the functional matrix, and in particular of growth-related expansion of the capsular matrices.

Schematic representation of the functional matrix hypothesis of craniofacial growth. Primary growth of the capsular matrix (brain) results in a stimulus for secondary growth of the sutures and synchondroses, leading to overall enlargement of the neurocranium (macroskeletal unit). Function of the temporalis muscle exerts pull on the periosteal matrix and f increasingly more comprehend bone growth of the temporal line (microskeletal unit).
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Debate about the functional matrix hypothesis was considerable during the 1960s and 1970s, primarily because it presented an entirely new way to consider craniofacial growth. Most of the criticism was directed primarily at only two general points. First was what appeared to be unnecessarily ambiguous terminology and reliance on overly simplistic assumptions about function. Second was the very extreme position with respect to the role of the cephalic cartilages in the growth of the craniofacial skeleton. y,
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The periodic incorporation of advances in the biomedical, bioengineering and computer sciences allow the creation of more comprehensive revisions of the functional matrix hypothesis. The following topics gradually included revising the hypothesis: 1. The role of mechanotransduction 2. The role of osseous connected celluluar network 3. The genomic thesis 4. The epigenetic antithesis and the resolving synthesis Servosystem Theory of Craniofacial Growth (1970) The last major theory of craniofacial growth to emerge, the servosystem theory, was developed by Alexandre Petrovic, a physicianscientist interested in the extrinsic and intrinsic hormonal factors that affect cartilage growth. Petrovics research came to focus on the nature of cartilage growth in the craniofacial complex, and especially of the growth of the secondary cartilage of the mandibular condyle. Through a comprehensive series of in vitro and in vivo experiments using research approaches, Petrovic and colleagues demonstrated that the growth of the mandibular condyle is highly adaptive and responsive to both extrinsic systemic factors and local biomechanical and functional factors. He and his colleagues also demonstrated that the growth of the primary cartilages of the craniofacial complex, such as the cranial base and nasal septum, was influenced significantly less by local epigenetic factors. The servosystem theory relies on the vocabulary of cybernetics to describe the growth of the craniofacial complex. Most simply, the servosystem theory is characterized by the following two principal factors: The hormonally regulated growth of the midface and anterior cranial base, which provides a constantly changing reference input via the occlusion, and The rate-limiting effect of this midfacial growth on the growth of the mandible. While growth of the mandibular condyle and of the sutures may be affected directly and indirectly by systemic hormones, growth of these structures is clearly more compensatory and adaptive to the action of extrinsic factors, including local function as well as the growth of other areas of the craniofacial complex. Reduced to its most fundamental principles, the servosystem theory can be summarized as follows: As the midface grows downward and forward under the primary influence of the cartilaginous cranial base and nasal septum, influenced principally by the intrinsic cell-tissue related properties common to all primary cartilages and mediated by the endocrine
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system, the maxillary dental arch is carried into a slightly more anterior position. This causes a minute discrepancy between the upper and lower dental arches, which Petrovic referred to as the comparator, that is, the constantly changing reference point between the positions of the upper and lower jaws.

Proprioceptors within the periodontal regions and temporomandibular joint perceive even a very small occlusal discrepancy and tonically activate the muscles responsible for mandibular protrusion. Activation of jaw protruding muscles acts directly on the cartilage of the mandibular condyle and indirectly through the vascular supply to the temporomandibular joint, stimulating the condyle to grow. The effect of the muscle function and responsiveness of the condylar cartilage is influenced both directly and indirectly by hormonal factors acting principally on the condylar cartilage and on the musculature.

Servosystem theory of craniofacial growth, with emphasis on the growth of the mandible. Anterior growth of the midface (a) results in a slight occlusal deviation between the maxillary and mandibular dentitions (b). Perception of this occlusal deviation by proprioceptors (c) triggers the protruder muscles of the mandible to become more active tonically (d) in order to reposition the mandible anteriorly. The muscle activity and the protrusion in the presence of appropriate hormonal factors (e) stimulate growth at the mandibular condyle (f).

This entire cycle is continuously activated as a servomotor as long as the midface-upper dental arch continues to grow and mature and appropriate extrinsic, hormonal, and functional factors remain supportive. Unlike the functional matrix hypothesis, which precipitated a paradigm shift in craniofacial biology and rests primarily on alternative epistemological propositions about the nature of causality in explaining craniofacial growth, the principal feature of the servosystem theory is its reliance on experimental verification of detailed hypotheses. The
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servosystem theory, represented as a cybernetic model, describes the current state of available data and information and also provides insight into where to look to test relationships. In other words, the major strength of the servosystem theory is that it provides a road map for future experimentation. Van Limborghs theory A multifactorial theory was put forward by Van Limborgh in 1970. According to him, the previously proporsed theories were not satisfactory, but each contains elements of significance that cannot be denied. He explained the process of growth and development in a view that combines all the existing theories. He supports the functional matrix theory, acknowledges some aspects of Sutural theory, and doesnt rule out the genetic involvement. Van Limborgh suggested the following five factors that he believed controls growth.

Intrinsic genetic factor: They are the genetic control of the skeletal unit themselves. Local epigenetic factor: Bone growth is determined by genetic control originating from adjacent structures like brain, eyes etc. General epigenetic factor: They are genetic factors determining growth from distant structures. Eg: Sex hormones, growth hormones. Local environmental factor: They are non genetic factors from local external environment. Eg: habits, muscle force General environmental factor: They are general non genetic influences such as nutrition, oxygen etc

The views expressed by Van Limborgh can be summarized in the following points: 1. Chondrocranial growth is controlled mainly by intrinsic genetic factors. 2. Desmocranial growth is controlled by 3. The cartilageneous part of the skull must be considered as the growth centres. 4. Sutural growth is controlled mainly by influences originating from the skull cartilages and from other adjacent skull structures. 5. Periosteal growth largely depends upon growth of the adjacent structures. 6. Sutural and periosteal growth are additionally governed by local non genetic environmental influences. Enlows expanding V principle Many facial bones or part of bone have a V shaped pattern of growth. The growth movements and enlargement of these bones occur
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towards the wide ends of the V as a result of differential deposition and selective resorption of bone. Bone deposition occurs on the inner side of the wide ends of the V and bone resorption on the outer surface. The V pattern of growth occurs in a number of regions such as base of the mandible, ends of long bones, mandibular body, palate etc. Maxilla: Vertical growth of the maxillary complex is due to continued apposition of alveolar bone on the free borders of the alveolar process as the teeth erupt. Transversely, additive growth on the free ends increases the distance between them. The buccal segments move downward and outward as the maxilla itself is moving downward and forward, following the principle of expanding V. Mandible: Transverse dimensions, after first year of life are mainly due to the growth at the posterior border in an expanding v pattern. The two ramus also diverge outward from below to above so that additive growth at the coronoid notch, coronoid process and condyle also increases the superior inter-ramal dimension.

Enlows counterpart principle The counterpart principle of craniofacial growth states that the growth of any given facial and cranial part relates specifically to other structural and geometric counterparts in the face and cranium. There are regional relationships throughout the whole face and cranium. If each regional part and its particular counterpart enlarge to the same extent, balanced growth occurs. This is the key to what determines the presence or lack of balance in any region. Many part-counterpart combinations exist throughout the skull, and these provide a meaningful and effective way to evaluate the growth of the face and the morphologic relationships among all its structural components.
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Imbalances in the regional relationship are produced by differences in

Amount Direction Time

of growth between the counterparts.

The different parts and their counterparts are : 1. Nasomaxillary complex relates to the anterior cranial fossa 2. Horizontal dimension of the pharyngeal space relates to the middle cranial fossa. 3. Middle cranial fossa and breadth of the ramus 4. Maxillary and mandibular dental arch 5. Bony maxilla and corpus of the mandible. 6. Maxillary tuberosity and the lingual tuberosity. Neutropic factor controlling growth The neurotropic factor involves the network of nerves (all kinds, motor as well as sensory) as links for feedback interrelationships among all the soft tissues and bone. The nerves are believed to provide pathways for stimuli that can trigger certain bone and soft tissue remodeling responses. It appears to function by transport of neurosecretory material along nerve tracts (analogous perhaps to the neurohumoral flow from the hypothalamus to the neurohypophysis along tracts in the infundibulum) or by an exoplasmic streaming within the neuron. In this way, feedback information is passed, for example, from the connective tissue stroma of a muscle to the osteogenic periosteum of the bone associated with that muscle. The "functional matrix" thereby operates to govern the bone's development. It is an interesting but yet incomplete hypothesis in need of more study. Revolution in Developmental Molecular Biology Modern developmental molecular biology began a major conceptual change in the early 1980s, with new discoveries relating to the role of neural crest cells and regulatory genetic factors during development. With the discovery of homeobox and other regulatory genes in the mouse, molecular and genetic research focusing on the development of the craniofacial complex in mammals virtually exploded. Homeobox genes, or Hox genes, contain highly conserved sequences of DNA that encode for certain transcription factors and signaling molecules that regulate expression of other genes during development. As predicted by the operon theory, homeobox and other regulatory genes are the master switches regulating development of fundamental elements associated with the presence and appearance of major body structures, including many of those found in the craniofacial complex. Significant advances in our knowledge about normal and abnormal craniofacial development have come about as a result of very recent research involving homeobox and other regulatory genes. Clearly, the changes in our thinking about the mechanisms of craniofacial
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development and growth that will occur as a direct result of recent and future discoveries of the role of homeobox genes in development have only begun. Clearly understanding of homeobox genes and other regulatory factors, and of the additional genes and associated features whose expression they regulate, is fundamental to an understanding of the mechanisms of craniofacial development. The role of the neural crest Although neural crest is a transient structure and consists of only a few cells, it plays an important role in the developmental biology. The neural crest forms according to the rostocraudal gradient along the body axis and releases a free moving mesynchymal cell that follow definite migration route at precise time of development finally reaching target embryonic site where they differentiate and develop. The neural crest was first described by His on a chick embryo and ever since its discovery, many studies have been done. During the process of neuralation, ectodermal cells thicken to form the neural plate. The neural crest can be divided into four functional domains. They are:
a) Cranial neural crest (CNC) Gives rise to various structures of

chondrocranium. These cells migrate dorsolaterally to produce the craniofacial mesenchyme that differentiates into the cartilage, bone, cranial neurons, glia, and connective tissues of the face. These cells enter the pharyngeal arches and pouches to give rise to thymic cells, odontoblasts of the tooth primordia, and the bones of middle ear and jaw. b) Trunk neural crest gives rise to pigment synthesizing melanocytes and dorsal root ganglion containing sensory neurons. c) Vagal and sacral neural crest giving rise to parasympathetic ganglia of gut. d) Cardiac neural crest- giving rise to melaonocytes, neurons and connective tissue Cells from the lateral border of the crest of the neuroectoderm dissociate to form a cell population called the neural crest cells. Neural crest cells are a population of highly pluripotent cells that plays an important role in the development of the vertebrate head. In mammals, neural crest cells are formed during neuralation when cells at the margins of the neural folds undergo an epithelial to mesenchymal transition following an inductive interaction between neural plate and presumptive ectoderm. Neural crest cells migrate extensively throughout the embryo in the four overlapping domains (cephalic, trunk, sacral, and cardiac), in the developing head the cephalic neural crest migrates from the posterior
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midbrain and hindbrain regions into the brachial arch system. The ectomesemchymal neural crest cells then interact with epithelial and mesodermal cell populations present within the arches leading to the formation of craniofacial bones, cartilages and connective tissues. So in short, we can say that each component of the face that is the forehead, nose, cheeks, lips, jaws, chin etc arises from the coordination of a variety of morphogenetic events which includes cell migration and extracellular matrix remodelling, proliferation and differentiation of neural crest derived mesenchyme into skeletal and connective tissues, the assembly of musculature and the beginning stages of organogenesis. It should be noted that the facial mesenchyme is derived principally from the neural crest cells and not from the embryonic third germ cells which is responsible for the development of most of the other parts of the body. Migration of the neural crest cells The neural crest cells migrate away from the neural tube and begin to migrate throughout the embryo. Unlike other cells in which the cell migration occurs in sheets, the migration of the neural crest cells occurs individually. So the mechanism for the neural crest cell migration is different than others and occurs in one of the following or all process. It generally occurs in three stages.
1. Initiation:

The neural crest cells undergo an epithelial to mesenchymal transition causing the cells to break free from the neural tube and in this process adhesion connection between the neural crest cells mediated by molecules such as N-CAM, N-Cadherin and E-Cadherin are down regulated. Simultaneously there is an increase in the junction between the neural crest and the extracellular matrix. This happens due to an increase in a protein integrin in the cell surface. The amount of the intercellular space increases and finally the neural crest cells become more motile. matrix to reach its fi nal destination where they proliferate and develop.

2. Dispersion: The neural crest cells migrate through the extracellular

3. Cessation

of migration: Occurs as a reverse of initiation of migration. The adhesive molecules i.e. NCAM, N-Cadherin and ECadherin are re-expressed. The amount of extracellular matrix is decreased and thus the migration is reduced.

The neural crest cells take either the ventral pathway or the dorsolateral pathway. The cells arising from the cranial or cephalic neural crest cell migrate dorsolaterlly to produce the craniofacial mesenchyme which gets differentiates into the cartilage, bone, cranial neurons, glia and connective tissues.

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Homeobox genes Homeobox genes were discovered independently by Walter J Gehring in 1983 working at the University of Basel, Switzerland and Matthew Scott and Amy Weiner who were working at Indiana University Bloomington. Homeobox is a 180 base pairs long DNA sequence found within genes that are involved in the morphogenesis in animals, plants and fungi. The homeobox encodes a 60-amino acid helix loop helix DNA binding within an encoded transcription factor. The region of the protein is the homeodomain and act as transcription factors that activate or inhibit the transcription of other genes. The homeobox genes were first identified in Drosophila melanogaster in which it was clustered in two segments (Antennapedia and bithorax) on chromosome no 3 and hence was known as HOM-C complex. The HOMC represented the molecular representation of the anterior posterior embryonic axis of the developing fly. Soon after this, a search began for similar genes in vertebrates. The homeobox genes have been classified in different ways into superclasses, classes, subclasses, or groups but there has been inconsistency the terms. The most widely used groupings are ANTP, PRD, LIM, POU, HNF, SINE, TALE, CUT, PROS and ZF. Also widely recognized gene families include Dlx, Msx, Otx, Hox, PAX, and NK. There are 11 classes of homeobox genes subdivided into 102 homeobox gene 'families' with a total of 300 human homeobox genes loci. Many more researches are still going in in developmental biology to clarify the growth.

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