Human life begins at fertilisation, when a fusion of an oocyte with a sperm occurs, forming a single cell called a zygote, from which a new individual organism will develop. This event usually occurs while the oocyte is still in the fallopian tube ( Fig. 12.1 ). Following fertilisation, a series of significant changes occur in the zygote, giving rise to an embryo. The development of the face and jaws is under a strong genetic influence. However, facial development is influenced and disrupted by environmental conditions. The knowledge of pre-natal development, more so of the face and associated structures, is fundamental to understanding the post-natal development of the face and how an orthodontist can choose the time and type of interventions to influence the growth with objectives to attain a harmonious face.

Initial stages of embryonic development from the time of fertilisation to implantation in the uterine mucosa.

It is the blastocyst stage at which implantation occurs within the uterine wall approximately 6 days after fertilisation.

The period of intrauterine development is divided into three major stages.

• 1.

  Pre-implantation period . The first 7 days following fertilisation.

• 2.

  Embryonic period . From the seventh day to the eighth week after fertilisation.

• 3.

  Foetal period begins around the ninth week and lasts until birth. During the ninth week of the term, the body structures of the foetus continue to grow and expand. However, there is little differentiation or the formation of new organs. During this period, ossification centres form, the first step in bone development. Additionally, the foetus begins to move during this time, marking an essential milestone in its development ( Fig. 12.2 ).

  

  The timeline and terminology used during the pre-natal and post-natal period.

During the first 2–3 days, the single celled zygote, 140 μm in size, divides progressively to form a 16-celled cluster called morula . With further cell division, the morula forms a 100-celled structure called a blastocyst , which implants in the uterus around the seventh day post-conception. A fluid-filled cavity develops within the blastocyst, which divides the cells into the outer sphere of cells and an inner cell mass. The outer sphere of cells forms the trophoblast , while the inner cell mass forms the embryo. The trophoblast is responsible for the development of the chorionic villi and, thus, is vital for the nutrition of the developing embryo.

During the embryonic period, the zygote develops into a multicellular organism called an embryo, and the basic body structures and organs begin to form. Weeks 4 through 8 are critical because most tissues and organ systems differentiate during the period from the original three germ layers ( Table 12.1 ).

The embryonic period can be further divided into the pre-somite, somite and post-somite phases.

• 1.

  Pre-somite phase : This phase encompasses the second and third weeks after fertilisation, characterised by the differentiation of the three germ layers and formation of the embryonic adnexa (foetal membranes) from the inner cell mass.

• 2.

  Somite phase : Lasts from the 21st to the 31st day, approximately the fourth week and early fifth week; characterised by the formation of the dorsal metameric segments of the body (neural tube, somites, etc.) an establishment of the basic body plan, polarity and patterns of the major organ systems.

• 3.

  Post-somite phase : Lasts from 32nd to 56th day; late fifth to eighth week; characterised by the development of external body features and further development and differentiation of the basic structure.

Carnegie stages of embryonic development

The embryonic period can also be divided, by the morphogenetic development of the embryo, into 23 stages starting from fertilisation ( Fig. 12.3 ). These are popularly known as Carnegie stages, named after Carnegie Institute of Washington, USA, and are based on the work of Streeter and O’Rahilly and Müller.

Selected Carnegie stages of human embryonic development from 28th to 56th day.

Carnegie stages divide the human embryonic period into 23 stages from the time of fertilisation to the beginning of the foetal period on the basis of important embryonic events.

During the second week, two important events take place.

• 1.

  The trophoblast layer (outer cell mass) starts to differentiate forming the outer layer of a blastocyst, which provides nutrients to the embryo, and develops into a large part of the placenta. They are comprised of two distinct cell populations: undifferentiated cytotrophoblasts and fully specialized syncytiotrophoblasts. Syncytiotrophoblasts form a continuous layer of specialized epithelial cells that come into direct contact with maternal blood. Cytotrophoblasts are found beneath the syncytiotrophoblasts and are regarded as the progenitor cells for syncytiotrophoblasts. Cytotrophoblasts undergo continuous differentiation into syncytiotrophoblasts during the process of villous formation and subsequent development.

• 2.

  The inner cell mass divides to form a bilaminar structure ( Fig. 12.4 ). The bilaminar structure is made of the epiblast (ectoderm), which consists of columnar cells and forms the floor of the amniotic cavity, and the hypoblast (endoderm), which consists of squamous or cuboidal cells forming the roof of the yolk sac. Meanwhile, the coelomic cavity develops in the extraembryonic mesoderm (loose tissue adjacent to the embryo), which enlarges progressively to surround the embryo except at the stalk, where the trophoblastic cells form the chorionic plate. This is the site where the chorion will develop later.

  

  Early stages of development of the human embryo.

  (A) Seven-day-old human blastocyst showing the trophoblastic and amniotic layers. A small amniotic cavity is developing. (B) Nine-day-old human blastocyst. The hypoblast layer extends to enclose a space called exocoelomic cavity (primary yolk sac). (C) Twelve-day-old blastocyst. The exocoelomic cavity and the amniotic cavity increase in size. The extraembryonic mesoderm fills the gap between the cytotrophoblast layer and the exocoelomic cavity. (D) Thirteen-day-old blastocyst. Formation of extraembryonic coelom occurs by the breakdown and coalescence of the fluid-filled spaces in the extraembryonic mesoderm. Cells from the hypoblast migrate to displace the exocoelomic cavity away from the embryo proper and encase a new space called the secondary yolk sac. The exocoelomic cavity is reduced into a remnant called the exocoelomic cyst.

By the end of the second week, the axis of the embryo starts to grow with the appearance of the node at the rostral end ( Fig. 12.5 ).

Section through 14-day-old embryo.

(A) Fourteen-day-old embryo. (B) Location of cut. (C) Cut section through the amniotic cavity of a third week embryo showing the dorsal surface of the embryo proper. The formation of the primitive node and the primitive streak defines the axis and the poles of the embryo. (D) Dorsal migration of the surface epiblast cells along the primitive streak towards the rostral end of the embryo (arrows). Subsequently, cells derived from the epiblast also invaginate between the epiblast and the hypoblast laterally to form the intraembryonic mesoderm (lines).

The node develops under the signalling influence of the following genes, including nodal, hedgehog, FGF (fibroblast growth factor), Wnt (wingless-int) and BMP (bone morphogenetic protein). The ventral node’s activity, facilitated by the ciliary movement of its cells, generates leftward fluid flow, known as nodal flow. This directional flow is instrumental in developing left–right asymmetry in the developing embryo. At the same time, localised thickening of the endoderm at the mid-cephalic region gives rise to the pre-chordal plate under the influence of the sonic hedgehog (Shh) gene. This pre-chordal plate has been shown to have a head-organising or molecular-organising function, producing signals that pattern the forebrain and help differentiate the eye fields. Signalling defects in this region are known to cause holoprosencephaly or agenesis of the corpus callosum. The pre-chordal layer also contributes to the formation of the endodermal layer to the oropharyngeal membrane (a membrane which separates the oronasal cavity from the pharyngeal cavity during early development).

Early in the third week, the epiblast proliferates and differentiates to give rise to the third layer of cells called the mesoderm through a process called gastrulation , thus establishing the trilaminar structure of the embryo.

The proliferation of the epiblast starts at the caudal end of the embryo, forming a caudocranial groove at the caudal end. This groove is called the primitive streak. As the primitive streak elongates, migrating epiblast cells join the streak at the cranial end, forming a mass of cells around the primitive pit called the primitive node. It marks the cranial limit of the primitive streak and serves as a vital signalling centre in early embryonic development, orchestrating gastrulation, establishing body axes and contributing to the formation of the notochord. From the primitive streak, the rapid proliferation of cells leads to the formation of the intraembryonic mesoderm, which proliferates in all directions between the ectoderm and the endoderm. The mesoderm layer is well established by the end of the third week. It separates the ectoderm and endoderm throughout the embryo except for two places: the cloacal membrane in the caudal region and the pre-chordal plate at the cranial midline area, where the endoderm and ectoderm are tightly adherent. The formation of the three germ layers is a critical landmark during the early development of the embryo. The pre-chordal plate is the future region of the buccopharyngeal membrane.

From henceforth, the further development of the embryo occurs through the growth and differentiation of the three primary germ layers, namely, ectoderm (first layer), mesoderm (second layer) and endoderm (third layer) ( Fig. 12.6 ). Neural crest (NC) layer, considered by some as the fourth germ layer, is essentially a derivative of the ectodermal layer. The derivatives emerging from the three germ layers are tabulated in Table 12.2 .

Sections through developing embryo in the third week.

(A) Mid-sagittal section of the embryo shows the development of the embryonal axis and the primitive notochord. (B, C) The transverse section shows the formation of the third germ layer and the developing notochord. (D) Transverse section through the cranial end of the primitive streak in a third-week embryo showing gastrulation (at the plane marked in Fig. 12.6A). Cells from the epiblast layer differentiate and migrate extensively between the epiblast and the hypoblast to form the intraembryonic mesoderm (the third germ layer).

Meanwhile, cells of the primitive streak proliferate further in a cranial direction and contact the pre-chordal plate. These cells further invaginate the underlying tissue to form a structure called the notochord. Notochord represents the early midline axis of the embryo, helping to establish the axial skeleton. It also induces the formation of the neural plate in the overlying ectoderm, which later gives rise to the neural ectoderm.

The effect of forkhead transcription factors (FoxC1 and FoxC2), along with neurogenic locus Notch homolog (NOTCH) pathway genes and homeobox (HOX) genes, leads to the condensation and conformational changes of paraxial mesoderm at the end of the third week of development, resulting in the formation of somites. This process occurs bilaterally on either side of the neural tube.

By the fourth week of embryonic development, the embryo enters the somite period, where approximately 38 pairs of somites can be observed. This number increases to about 44 pairs by the end of the fifth week. Somites are particularly distinctive because they create noticeable elevations on the dorsal surface of the embryo. Their prominence is also useful for estimating the age of the embryo during the fourth and fifth gestational weeks.

The somite period is characterised by establishing the primordia of the most important organ systems like the gut, kidneys, adrenals, heart, lungs and others.

Between the 21st and 31st days, the embryo changes its form from a flat disc to a tubular structure. Simultaneously, the rapid growth of the developing central nervous system on the dorsal aspect leads to the folding of the embryo over its ventral aspect, thus forming a C-shaped structure at around 4 weeks ( Fig. 12.7 ). The folding leads to incorporating the secondary yolk sac into the embryonic structure. The secondary yolk sac contributes to the formation of the gut.

Schematic diagram showing the folding of the embryo over its ventral aspect due to exaggerated growth on the dorsal aspect.

*C = caudal; R = rostral.

Neurulation

Development of the neural plate, neuroectoderm and neural tube are the processes of neurulation . During the third week of development, the notochord induces the overlying ectoderm to thicken and differentiate into the neural plate.

The process of neurulation is composed of primary and secondary neurulation. While primary neurulation is associated with the formation of a hollow tube by the proliferation of cells of the neural plate, secondary neurulation leads to the formation of the medullary cavity (neural tube) from a solid core of cells. Both processes are different, although interlinked intricately.

The developing neural tube consists of three sets of cells: (1) the inner layer of cells (neural tube), which will form the future spinal cord and the brain; (2) NC cells; and (3) epidermal cells. The NC cells eventually migrate across the embryo and have a significant role in the development of the facial structure, apart from the development of peripheral neurons.

The neurulation process can be divided into four distinct but spatially and temporally overlapping stages:

• 1.

  formation of the neural plate,

• 2.

  shaping of the neural plate,

• 3.

  bending of the neural plate to form the neural groove and

• 4.

  closure of the neural groove to form the neural tube.

The neural plate grows caudally towards the primitive streak ( Fig. 12.8 ). Around the 20th day post-conception, the lateral edges of the neural plate elevate to form the neural folds, enclosing a neural groove in the midline ( Fig. 12.9 ).

Schematic representation of dorsal embryonic development during neural plate formation.

(A) Early stage showing the primitive streak with minimal regression, while the embryo and neural plate begin to enlarge. The notochord begins to form at the cephalic end of the primitive streak through the process of cell ingression. (B) As the embryo elongates, the notochord extends anteriorly towards the future oropharyngeal membrane. Molecular signals from the notochord and surrounding mesenchyme induce the overlying ectoderm to differentiate into the neural plate. (C) With continued embryonic growth, the primitive streak appears reduced in relative size, and the notochord elongates further. The neural plate expands, especially in its anterior region, creating a broad cranial domain compared to the narrower newly formed posterior region near the primitive streak.

Source: DeSesso JM, Williams AL. Periods of Susceptibility: Interspecies Comparison of Developmental Milestones During Ontogenesis of the Central Nervous System. In: Handbook of Developmental Neurotoxicology. 2nd ed. 2018;113-125. Academic Press.

The transverse section through the developing embryo shows the folding of the neural plate to form the neural tube. MHP medial neural hinge point; DLHP dorsolateral hinge point.

Source: Based on the concept of Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Formation of the Neural Tube. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10080 /

On the 22nd day post-conception, the neural folds start to fuse with the counterpart of the other side over the neural groove. The fusion occurs first in the region of the future occipital area (area of third to fifth somites) and proceeds both cranially and caudally to produce the neural tube. The neural tube is the primordium of the central nervous system, and its anterior end enlarges to form the three segments of the brain: forebrain, midbrain and hindbrain. Around the same time, the lens and otic placodes begin to form as outgrowths from the ectoderm at the cranial end of the embryo. These later give rise to the eye and the inner ear, respectively.

The closure of the human neural tube is a complex process influenced by genetic and environmental factors. Key genes, including paired box 3 (PAX3), SHH and openbrain (opb), are vital in forming the mammalian neural tube. Additionally, dietary elements such as cholesterol and folic acid are recognised as critical contributors. Research suggests that supplementing nutrition with folic acid during pregnancy can reduce human neural tube defects by approximately 50%. The US Public Health Service recommends a daily intake of 0.4 mg of folate for all women of childbearing age to mitigate the risk of neural tube defects during pregnancy.

Development of the neural crest

NC refers to a unique collection of cells that arise in the crest of the neural folds during the process of neurulation ( Fig. 12.10 ). It consists of pluripotent cells, ectomesenchyme in origin, induced by interaction between Wnt activation and BMP inhibition signal pathways. These cells are characterised by their tendency to extensively migrate along the natural cleavage planes between the three germ layers, usually beginning at about the time of closure of the neural tube ( Fig. 12.11 ). They divide as they migrate, giving rise to cell masses, which are much bigger at the destination than at their origin. Once they reach their pre-determined location, they differentiate into specific tissues according to the morphogenetic fields, giving rise to many vital tissues in the head and neck ( Fig. 12.12 ) and the trunk region ( Table 12.3 ). Consequently, the NC has long been designated the ‘ fourth germ layer ’ despite originating from the ectoderm.

Schematic diagram of a transverse section through the dorsal end of an embryo showing the formation of the neural crest cells (neurulation) in the lateral aspect of the neural folds.

Schematic diagram showing neural crest cell migration in the trunk region of chick embryo.

Path I cells travel ventrally through the anterior portion of the sclerotome. Path II cells travel along a dorsolateral route below the surface ectoderm.

Source: Reproduced with permission from Gilbert SF, Sunderland MA (eds). Developmental Biology, 6th ed., Sinauer Associates, 2000 .

(A) Migration of the cranial neural crest cells into the head and the branchial arches to form structures of the face and neck, including bones and cartilage. They also produce pigment cells and cranial nerves. Source for Fig A: Adapted from Gilbert SF, Sunderland MA (eds). Developmental Biology, 6th ed, Sinauer Associates, 2000 (B) Shows origin of structures from first to fourth pharyngeal arch. ML: Malleus, IN: Incus ST: Stapes.

Source for for B: https://upload.wikimedia.org/wikipedia/commons/e/e1/Cranial_Neural_Crest_Cells_-_ migration.jpg

TABLE 12.3

Pharyngeal arches: Derivatives of cranial neural crest and trunk neural crest

Source: Adapted from Carlson BM. Foundations of Embryology. 6th ed. India: Tata McGraw Hill; 2007.

Organ system	Cranial neural crest	Trunk neural crest
Muscles	Ciliary, dermal smooth muscles and vascular smooth muscles	Nil
Mesodermal cells (connective tissue)	Dermis, fat, smooth muscles of skin, ciliary muscles of eye, cornea, connective tissue of glands of head and neck; odontoblasts, part of prosencephalon and mesencephalon	Nil
Mesodermal cells (skeleton)	Cranial vault; nose and orbit skeleton; otic capsule; maxilla, minor part of sphenoid	Nil
Endocrine system	Calcitonin producing cells, carotid body (type I cells); parafollicular cells of thyroid	Adrenal medulla; neurosecretory cells of heart and lungs
Pigment cells	Melanophores, xanthophores, erythrophores and iridophores	Melanophores, xanthophores, erythrophores and iridophores
Nervous system	Sensory ganglia of cranial nerves: V, VII, IX, X; satellite cells of sensory ganglia, parasympathetic ganglia of cranial region: oligodendroglia	Sensory spinal ganglia; satellite cells of these ganglia; parasympathetic ganglia of trunk region; Schwann cells of peripheral neurons

NC cells originate from four major segments of the neural tube, giving rise to cranial (or cephalic), vagal, trunk and sacral NC cells.

• 1.

  Cranial NC cells originate from the diencephalon, midbrain and hindbrain regions. These cells have the ability to differentiate into various craniofacial structures, such as bones, cartilage and connective tissue. The rostral cranial NC cells extensively contribute to the formation of frontonasal skeleton. In contrast, the posterior cranial NC cells contribute to the formation of structures within the pharyngeal arches, including thymic cells, odontoblasts of the tooth primordia and the bones of middle ear and jaw. They also play a role in forming membranous bones within the skull vault.

• 2.

  Trunk NC cells originate from the posterior part of the embryo, and it give rise to pigment cells in the skin, contribute to the development of the peripheral nervous system and formation of secretory cells within the endocrine system.

• 3.

  Vagal and sacral NC cells, originating from somites 1 to 7 (vagal) and posterior to somite 28 (sacral), are considered to exhibit characteristics of both cranial and trunk NC cells. These vagal NC cells give rise to various cell types found in the thymus, thyroid, parathyroid and heart. Additionally, they contribute to ganglia formation in the lung, pancreas and gastrointestinal tract.

• 4.

  Cardiac NC cells, originating from the dorsal neural tube located between the otic vesicle and the third somite within the vagal crest segment, are vital for cardiac development.

Development of the skeleton

Following the formation of the neural plate and the notochord, the intraembryonic mesoderm differentiates into three types of cell masses depending on the following:

• •

  Lateral plate mesoderm

• •

  Intermediate mesoderm

• •

  Paraxial mesoderm

The lateral plate mesoderm and the intermediate mesoderm give rise to a variety of tissues and organs throughout the body.

The paraxial mesoderm is of particular interest to dental professionals as it is intimately associated with the development of the cranial structures.

Paraxial mesoderm develops adjacent to the notochord along the dorsal surface of the embryo. On further differentiation, its rostral end gives rise to elevated masses of tissues in the cranial region called the somitomeres. These somitomeres are situated in the paraxial region of the notochord. The caudal paraxial mesoderm gives rise to similar structures called somites in the more caudal part of the embryo. Each somite has three essential parts differing in location, each of which gives rise to different tissues:

• 1.

  Sclerotome: Ventromedial part; gives rise to the vertebral region except in the occipital region.

• 2.

  Dermatome: Lateral part; gives rise to the dermis of the skin.

• 3.

  Myotome: Intermediate portion; gives rise to the muscles of trunk and limbs, and some craniofacial muscles.

Approximately 42–44 paired somites are known in a human embryo, of which four are occipital and eight are cervical (somitomeres in the craniofacial region) ( Fig. 12.13 ).

Somites.

Schematic representation of a 29-day-old embryo from the dorsal aspect showing the somites.

Adapted from https://quizlet.com/708390384/midterm-lect-11-development-of-muscles-flash-cards/

Pharyngeal arches

Development of the neck tissues and a major part of the face largely depends on the cranial somitomere’s mesoderm. The cells of the somitomere mesoderm migrate into the ventral region of the embryo at the rostral end and, with a minor contribution from the lateral plate mesoderm, in the formation of the future pharyngeal arches.

During the fourth week of intrauterine life, the pharyngeal arches arise as outgrowths on the ventral surface of the embryo, rostral to the foregut and in relation to the ventral surface of the rhombencephalon.

Each pharyngeal arch has all three embryologic cell layers. The ectoderm forms the pharyngeal groove or cleft, while the endoderm forms the pharyngeal pouch. Between the two layers lies a mesodermal core containing mesodermal cells and NC cells. Mesodermal cells are responsible for the formation of a large variety of body structures. In contrast, NC cells are responsible for the development of large parts of head and neck structures. These NC cells are derived from specific hindbrain (rhombomere) segments with minor overlap between segments.

NC cells from rhombomeres 1 and 2 and caudal midbrain-derived crest cells populate the first branchial arch. Crest cells from rhombomere 4 populate the second arch, while rhombomere 6 and 7 contribute to third, fourth and sixth pharyngeal arches. It should be noted that rhombomeres 3 and 5 are depleted of NC cells and whatever little cells they produce die by apoptosis under the influence of gene BMP4.

Each pharyngeal arch has its specific apparatus: a specific cartilage that forms the skeleton of the arch, a nerve that supplies the muscles and mucosa derived from the arch and an artery (called the aortic arch) ^, ( Fig. 12.14 ). All these components are well developed in the first and second arches except for the arteries. ^, Pharyngeal arches play a major role in the formation of a face, oral cavity, teeth, nasal cavity, pharynx, larynx and neck ( Tables 12.4 and 12.5 ; Fig. 12.15 ).

Branchial arches.

(A) A developing embryo showing branchial arches. Dotted lines shows the location of the slice. (B) Cut section through the branchial arches in a developing embryo. Each arch has its own neural, vascular supply and cartilage. The arches are grooved on the external surface by pharyngeal clefts and on the internal surface by pharyngeal pouches. The arches are lined externally by ectoderm and internally by endoderm, between which lies each arch’s mesodermal core. The fifth arch disappears during development.

TABLE 12.4

Major neural crest derivatives

Source: Modified from Hiatt JL, Gartner LP. Textbook of Head and Neck Anatomy. 3rd ed. Lippincott Williams & Wilkins: Baltimore; 2001.

Arch	Cartilage; derivatives	Bone	Muscles	Nerve
First	Meckel’s cartilage; derivatives: sphenomandibular ligament, anterior ligament of malleus	Maxilla, mandible, malleus and incus	Masticatory muscles: temporalis, masseter and the pterygoids, tensor palatini, tensor tympani and anterior belly of digastric	Trigeminal (V)
Second	Reichert’s cartilage; derivatives: stylohyoid ligament	Lesser cornu and body of hyoid	Muscles of facial expression, stapedius, posterior belly of digastric and stylohyoid	Facial (VII)
Third	–	Greater cornu and body of hyoid	Stylopharyngeus	Glossopharyngeal (IX)
Fourth and sixth	Thyroid cartilage; laryngeal cartilages		Pharyngeal and laryngeal muscles	Recurrent laryngeal n. (Br. of CN X), spinal accessory (XI) via the pharyngeal br. of CN X

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