CONTENTS

1. Introduction
2. BONE GROWTH AND HEREDITY (1920-1940)
a. GENETIC THEORY
b. Remodeling theory
c. Beginning of developmental genetics
3. Alternate viewpoint (1940-1960)
a. Sutural theory
b. Nasal septum theory
c. Gene structure and action
4. Paradigm shift (1960-1980)
a. Functional matrix hypothesis
b. Servosystem theory
c. Van limborghs study
d. Enlows Expanding V principlE
e. Enlows countErpart principlE
5. Newer concepts
a. Functional matrix revisited
b. Neurotrophism
c. Bioelectric theory
d. Growth relativity
e. maos concEpt
f. rabiEs concEpt
g. Homeobox genes
6. Conclusion
7. references

1
THEORIES OF GROWTH

Presented by :

Dr. Adittee Shukla

PG student 1st year,

Guided by :

Dr. Shruti Mittal Dr. Ruchi Nayar

H.O.D. Professor

Department of Orthodontics and Dentofacial Orthopaedics

Swami Devi Dyal Hospital and Dental College, Barwala.

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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 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 the
environment in the form of nutritional status, degree of physical activity, health or illness,
and a number of similar factors also can significantly affect it. 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.

The major theories explaining growth are

1. Genetic Theory
2. Remodelling Theory
3. Sutural Theory
4. Cartilaginous Theory
5. Functional matrix Theory
6. Functional matrix revisited
7. Sevosystem Theory
8. 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
4. Bioelectric theory
5. Growth relativity
6. Maos concept
7. Rabies concept

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 8. Homeobox genes

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 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)

Weinmann and Sicher, two prominent anatomists, proposed the sutural theory.
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
condylar 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.

Cartilaginous 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.

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

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 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.

II. 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 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 with in 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."

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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.

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.

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The principles of 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.
There are also two categories of skeletal units:
(1) microskeletal units and
(2) macroskeletal units.

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 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.

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,

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 cellular 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 Alexander Petrovic, a physician-scientist 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.

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 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 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.

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
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.

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Van Limborghs theory

A multifactorial theory was put forward by Van Limborgh in 1970. According to him, the
previously proposed 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 cartilaginous part of the skull must be considered as the growth centers.
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 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

11
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.
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

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 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 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
rosto-craudal gradient along the body axis and releases a free moving mesenchymal 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 melanocytes, 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

13
pluripotent cells that plays an important role in the development of the vertebrate head. In
mammals, neural crest cells are formed during neurulation 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
midbrain and hindbrain regions into the branchial 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.

2. Dispersion: The neural crest cells migrate through the extracellular matrix to reach
its final destination where they proliferate and develop.

3. Cessation of migration: Occurs as a reverse of initiation of migration. The adhesive

molecules i.e. NCAM, N-Cadherin and E-Cadherin 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 cells 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 on in developmental biology to clarify the growth.

Functional matrix revisited

Advances in biomedical, bioengineering and computer sciences made Moss to do a

comprehensive revision of the functional matrix hypothesis. Incompleteness with functional
matrix hypothesis was that it did not describe how functional stimuli are converted into
controlling signals by individual bone cells and how these cells communicate to produce
coordinated multicellular responses. Old functional matrix hypothesis had a hierarchical
constraint:
Initial explanations did not extend downward to processes occurring at the
cellular, subcellular or molecular level nor extends upwards to the multicellular processes
by which bone tissues respond to lower level signals. It had hierarchical constraints.

Mechanotransduction is a process by which cells convert external stimulate in the form of a

load into an intercellular signal. Static and dynamic loadings are continuously applied to
bone. When stimulus exceeds threshold values, loaded tissue responds by triad of bone cell
adaptation, resorption and maintenance. Thus osseous mechanotransduction translates
information of periosteal functional matrix stimulus into a skeletal unit cell signal, i.e it
moves information hierarchically downward to the osteocytes.
There are two osseous mechanotransductive processes;
1. Ionic
2. Mechanical-by integrins ,actins, gap junctions,

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A genomic thesis/epigenetic antithesis and a resolving synthesis were done by Moss.
RESOLVING SYNTHESIS suggests that both genomic and epigenetic factors are necessary and
neither alone is sufficient cause.

CONCLUSION

Various theories propounded over the past centuries were based primarily on
incomplete assumptions on the nature of heredity and inheritance of craniofacial growth.
Because of the significant lag between discoveries in the field of genetics and their
incorporation into the concepts of growth modification a paradigmatic shift to the cellular
level of understanding these theories occurred quite late. Its now clear that the number of
genetically encoded regulatory factors affect morphogenesis and prenatal development of
craniofacial complex acting within the milieu of epigenetic factors. There is a plethora of
evidence that growth can now be modified. However this does not necessarily mean that it
can be modified in a predictable, controlled and clinically effective way. Craniofacial
complex grows and adapts within an epigenetic milieu that include genes, environmental
and functional factors, but within the parameters that are regulated by the genome.

What remains now is to understand how these genomic and epigenetic factors can
be engineered biologically and introduced into individual treatment needs at appropriate
time to produce clinically desired effect.

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