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The prenatal period is divided into two major periods: the embryonic period, from fertilization through
2 months, and the fetal period, from the third month through birth.
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The embryonic period is the time when all tissue is formed and, particularly during the second month, when all
organs are formed. The fetal period is a time of organ growth.2 Embryologic development begins with
fertilization, the process by which the male and female gametes unite to give rise to a zygote. Approximately 3 days
after fertilization cells of the compacted embryo divide to form a morula, which is composed of an inner and
outer cell mass. The inner cell mass gives rise to the tissues of the embryoblast, and the outer cell mass
forms the trophoblast, which later contributes to the placenta. After a period of cell division, during
which time the morula enters the uterine cavity, the blastocoele forms, and the embryo is known as a
blastocyst (Figure 2–1).
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By the eighth day of development the blastocyst is partially embedded in the endometrium. At this time the
trophoblast differentiates into an inner and an outer layer. Lacunae develop in the outer layer, maternal sinusoids
are eroded, and by the end of the second week a primitive uteroplacental circulation begins to develop.
++
The inner cell mass, or embryoblast, differentiates into two layers, the epiblast and the
hypoblast, which together form the bilaminar germ disk.
++
The most characteristic event occurring during the third week of gestation is gastrulation. This is the
process that establishes all three germ layers: endoderm, ectoderm, and mesoderm in the embryo
(Figure 2–2). Gastrulation begins with the formation of the primitive streak on the surface of the epiblast
portion of the bilaminar germ disk. Cells migrate toward the primitive streak, detach from the epiblast, and slip
beneath it. This inward movement is known as invagination. Once the cells have invaginated, some displace
the hypoblast, creating the new embryonic endoderm. Other cells come to lie between the epiblast and the newly
created endoderm to form the mesoderm. Cells remaining in the epiblast then form the ectoderm. Through the process of
gastrulation, the epiblast therefore, becomes the source of all the germ layers in the embryo.1 Developments
during the first 3 weeks of the embryonic period therefore produce an embryo with: one germ layer (week 1), two germ
layers (week 2) and three germ layers with a recognizable three-dimensional body form (week 32 (Figure 2–3).
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In general terms the ectoderm germ layer gives rise to organs and structures that allow us to maintain
contact with the outside world.4 It gives rise to the central and peripheral nervous systems; the sensory
epithelium of the eye, ear and nose; the epidermis and its appendages; hair and nails, mammary glands; the
hypophysis, subcutaneous glands; and the enamel of the teeth.
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The mesoderm gives rise to supporting structures of the body, such as cartilage, bone, and connective
tissue; striated and smooth muscle; the heart, blood, lymph vessels, and cells; the kidneys, gonads, and serous
membranes lining the body cavities, spleen, and the cortex of the adrenal gland.
++
The endoderm produces the epithelial lining of the gastrointestinal and respiratory tracts, as well as the
epithelial lining of the bladder and urethra, tympanic cavity, antrum, and auditory tube. It also engenders the
parenchyma of the tonsils, thyroid, parathyroid thymus, liver, and pancreas.
++
As the embryo forms, it rapidly develops along several axes,2 the first of which is the craniocaudal axis. It is
established while the embryo is still a flat disk or sheet of cells. This axis runs from the future head to future
tail of the body form. The dorsoventral axis is the next to be established. This occurs as the body folds and defines
the future front and back sides of the body form.
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Establishment of the body axes takes place prior to and during the period of gastrulation. Cells at the posterior
margin of the embryonic disk signal the craniocaudal axis. The dorsoventral orientation of tissue is controlled by a
complex interaction of proteins and growth factors.
++
This early orientation of cells in the body is a result of the expression of Hox genes. There are four Hox gene
complexes in vertebrates: Hoxa, b, c, and d. Each consists of a group of between 9 and 11 genes
arranged sequentially along a particular chromosome. A cascade of genes producing signaling factors also orchestrates
left–right asymmetry, which is established early in development. As a result of complex interactions, for example,
the heart and spleen lie on the left side of the body and the main lobe of the liver lies on the right.
++
Regions of the epiblast that migrate and ingress through the primitive streak have been mapped and their ultimate
fates determined. Mesoderm cells that ingress through the cranial region of the primitive node become the notochord,
those migrating at the lateral edges of the primitive node and from the cranial end of the primitive streak become
the paraxial mesoderm. Cells migrating through the midstreak region become the intermediate mesoderm, and those
migrating through the caudal part of the streak form the lateral plate mesoderm. This orientation of the mesoderm is
important in understanding limb development.
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The embryonic disc, initially flat and almost round, gradually becomes elongated, with a broad cephalic and a narrow
caudal end. Expansion of the embryonic disk occurs mainly in the cephalic region. This growth in elongation is caused
by continuous migration of cells from the primitive streak region in a cephalad direction. Invagination and migration
forward and laterally of surface cells in the primitive streak continue until the end of the fourth week. Germ cell
layers in the cephalic region begin their specific differentiation by the middle of the third week, whereas those in
the caudal part differentiate beginning by the end of the fourth week. This causes the embryo to develop in a
cephalocaudal direction (Figure 2–4).
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At the beginning of the third week of development the ectodermal germ layer has the shape of the disk. The ectoderm
gives rise to two subdivisions: neuroectoderm, which forms all neural tissue, and the epidermal covering of the
body.2 Appearance of the notochord and prechordal mesoderm induces the overlying ectoderm to thicken and
form the neural plate (Figure 2–5). Cells of the neural plate make up the neuroectoderm, and their induction
represents the initial event in the process of neurulation. By the end of the third week the lateral edges
of the neural plate become elevated to form neural folds, and the depressed midregion forms the neural groove.
Gradually, the neural folds approach each other in the midline where they fuse, resulting in formation of the neural
tube. Neurulation is then complete, and the central nervous system is represented by a closed tubular structure with
a narrow caudal portion, the spinal cord, and a much broader cephalic portion characterized by a number of dilations,
the brain vesicles. As the neural folds elevate and fuse, cells at the lateral border begin to dissociate from their
neighbors. This cell population, called the neural crest, will undergo a transition as they leave the
neuroectoderm to enter the underlying mesoderm.
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During the body-folding process, the endoderm is formed into an epithelial tube, which runs the length of the body.
The derivatives of the endoderm tube are all epithelial tissues (Figure 2–6).
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Initially cells of the mesoderm germ layer form a thin sheet of tissue on each side of the midline.1 These
cells proliferate and form a thick end plate of tissue known as paraxial mesoderm (Figure 2–7). More laterally the
mesoderm remains thin and is known as the lateral plate. This lateral plate divides into two layers: a somatic, or
parietal, mesoderm layer and a splanchnic, or visceral, mesoderm layer. Together these layers form the intraembryonic
cavity. Intermediate mesoderm connects the paraxial and lateral plate mesoderm.
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By the beginning of the third week, paraxial mesoderm is organized into segments. These segments are known as
somitomeres. They first appear in the cephalic region of the embryo, and their formation proceeds in a
craniocaudal direction. In the head region, somitomeres transition, in association with segmentation of the neural
plate, into neuromeres. From the occipital region caudally, somitomeres further organize into somites.
Somites give rise to the myotome (ultimately muscle tissue), sclerotome (ultimately cartilage and
bone), and dermatome (ultimately subcutaneous tissue of the skin). Collectively, these are all supporting
tissues of the body (Figure 2–8).
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Signaling for this somite differentiation arises from surrounding structures, including the notochord, neural tube,
epidermis, and lateral plate mesoderm. By the beginning of the fourth week cells forming the ventral and media walls
of the somite lose their compact organization and shift their position to surround the notochord (the dense cord of
mesoderm that induces neuroectoderm). These cells, collectively known as the sclerotome, form a loosely woven tissue
called the mesenchyme. They will surround the spinal cord and notochord to form the vertebral column. Cells at the
dorsolateral portion of the somite also migrate as precursors of limb and body wall structures. Following migration
of these muscle cells and cells of the sclerotome, cells at the dorsomedial portion of the somite proliferate and
migrate down the ventral side of the remaining dorsal epithelium of the somite to form a new layer, the myotome. The
remaining dorsal epithelium forms the dermatome, and together these layers constitute the dermomyotome. Each
segmentally arranged myotome contributes to muscles of the back, whereas the dermatomes disperse to form the dermis
and subcutaneous tissue of the skin. Each myotome and dermatome retains its innervation from the segment of origin,
no matter where the cells migrate to. Therefore, each somite forms its own sclerotome, the cartilage and bone
component; its own myotome, providing the segmental muscle component; and its own dermatome, the segmental skin
component. Each myotome and dermatome also has its owns segmental nerve component (Figure 2–9).
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During the second month, the external appearance of the embryo is changed greatly by the enormous size of the head
and formation of the limbs, face, ears, nose, and eyes.1 By the beginning of the fifth week, fore- and
hindlimbs appear as paddle-shaped buds (Figure 2–10). The forelimbs are located dorsal to the pericardial swelling
at the level of the fourth cervical to first thoracic somites, which explains their innervation by the brachial
plexus. Hindlimb buds appear slightly later just caudal to the attachment of the umbilical stock at the level of the
lumbar and uppers sacral somites. With further growth the terminal portions of the buds flatten, and a circular
constriction separates them from the proximal, more cylindrical segment. Soon four radial grooves separating five
slightly thicker areas appear on the distal portion of the buds. This development foreshadows formation of the
digits. These grooves, known as rays, appear in the hand region first, and shortly afterward, in the foot because the
upper limb is slightly more advanced in development than the lower limb. While fingers and toes are being formed, a
second constriction divides the proximal portion of the buds into two segments, and the three parts characteristic of
the adult extremities can be recognized.
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The period from the beginning of the ninth week to the end of the intrauterine life is known as the fetal
period.1 It is characterized by maturation of tissues and organs and rapid growth of the body growth in
length. This is particularly striking during the third, fourth, and fifth months, and increasing weight are most
striking during the last 2 months of gestation. During the third month the face becomes more human-looking, and the
limbs reach their relative length in comparison with the rest of the body, although the lower limbs are still a
little shorter and less well developed than the upper extremities. Primary ossification centers are present in the
long bones and the skull by the twelfth week.
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Skeletal System: Limb Growth & Development
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The skeletal system develops from paraxial and lateral plate mesoderm as well as neural crest tissue.1
++
The somites (as previously described) differentiate into a ventromedial component called the sclerotome and a
dorsolateral component called the dermomyotome. This organization of cells forms a loosely woven tissue called the
mesenchyme. The mesenchyme migrates and differentiates into fibroblasts, chondroblasts, and osteoblasts.
++
At the end of the fourth week of development limb buds become visible as out-pocketings of the ventrolateral body
wall.1 Initially they consist of a mesenchymal core derived from the somatic layer of lateral plate mesoderm
that will form the bones and connective tissue of the limb, covered by a layer of ectoderm. Ectoderm at the distal
border of the limb thickens and forms a specialized inducing tissue known as the apical ectodermal ridge
(AER). The AER exerts an inductive influence on the adjacent mesenchyme, causing it to remain as a population of
undifferentiated, rapidly proliferating cells called the progress zone. As the limb grows, cells farther
from the influence of the AER begin to differentiate into cartilage and muscle. In this manner of development of the
limb proceeds proximodistally. In 6-week-old embryos, the terminal portion of the limb buds become flattened to form
hand and footplates and are separated from the proximal segment by a circular constriction. Later a second
constriction divides the proximal portions into two segments, and the main parts of the extremities can be
recognized.1 Fingers and toes are formed when programmed cell death in the AER separates this ridge into
five parts. Further formation of the digits depends on their continued outgrowth under the influence of the five
remaining segments of ridge ectoderm. This results in condensation of the mesenchyme to form cartilaginous digital
rays. Development of the upper and lower limbs is similar except that morphogenesis of the lower limb is
approximately 1–2 days behind that of the upper limb.
++
During the seventh week of gestation a key event occurs that is critical in understanding the final orientation and
innervation of the limbs. The limbs rotate in opposite directions. The upper limb rotates 90 degrees
laterally so that the extensor muscles lie on the lateral and posterior surface and the thumbs lie
laterally. The lower limb rotates approximately 90 degrees medially, placing the extensor muscles on the
anterior surface and the great toe medially.1 This explains why homologous joints of the upper and
lower extremities (knees and elbows) point in opposite directions. This limb rotation results in:2
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The final orientation of the limbs
The final location and orientation of muscle groups (because the muscles are connected to the limb bones prior to
rotation)
The patterns of sensory innervation of the skin (also because nerve fibers are connected with the dermis layer of
the skin prior to rotation and are pulled along)
++
While the external shape is being established, mesenchyme in the buds begins to condense, and by the sixth week
of development the first hyaline cartilage models can be recognized. Ossification of the bones of the extremities
begins by the end of the embryonic period. Primary ossification centers are present in all long bones of the limbs by
the twelfth week of development.
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Molecular Regulation of Limb Development
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Positioning of the limbs along the craniocaudal axis in the flank regions of the embryo is regulated by the Hox
genes expressed along this axis.1 Once positioning along this axis is determined, growth must also be
regulated along the proximodistal, anteroposterior, and dorsoventral axes. Patterning of the anteroposterior axis of
the limb is regulated by the zone of polarizing activity (ZPA), a cluster of cells at the posterior border
of the limb near the flank. These cells produce retinoic acid, which initiates expression of sonic hedgehog
(Shh), a secreted factor that regulates development along this axis.1 This regulation results in digits
appearing in the proper order, with the thumb on the radial (anterior) side. As the limb grows, the ZPA moves
distally to remain in proximity to the posterior border of the AER. The dorsoventral axis is patterned in a similar
fashion by the dorsal ectoderm of the limb.
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Although patterning genes for the limb axes have been predetermined, it is the Hox genes that regulate the types
and shapes of the bones of the limbs. These Hox genes are nested in overlapping patterns of expression that somehow
regulate patterning.1 As a result, variations in their combinations create patterns of expression that may
account for differences in fore and hind limb structures.
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During the fourth week of development, cells of the sclerotome shift their position to surround both the spinal
cord and the notochord.1 During further development, the caudal portion of each sclerotome segment
proliferates extensively and condenses. This proliferation is so extensive that it proceeds into the subjacent
intersegmental tissue and binds the caudal half of one sclerotome to the cephalic half of the adjacent sclerotome. By
incorporation of this intersegmental tissue into the precartilaginous vertebral body, the body of the vertebrae
becomes intersegmental (Figure 2–11). Hox genes also control this patterning. Mesenchymal cells between cephalic and
caudal parts of the original sclerotome form the intervertebral disk. Although the notochord regresses entirely in
the region of the vertebral bodies, it persists and enlarges in the region of the intervertebral disk. Here it
contributes to the nucleus pulposus, which is later surrounded by circular fibers of the anulus fibrosus. Together
these structures form the intervertebral disk.1
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Muscular & Peripheral Nervous Systems
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With the exception of some smooth muscle tissue, the muscular system develops from the mesoderm germ
layer.1 Skeletal muscle is derived from paraxial mesoderm, which forms somites from the occipital to sacral
regions and somitomeres in the head. The somites and somitomeres form the musculature of the axial skeleton body
wall, limbs, and head. From the occipital region caudally, somites form and differentiate into this sclerotome,
dermatome, and two muscle forming regions. One of these is in the dorsolateral region of the somite and provides
progenitor cells (myoblasts) for the limb and body wall musculature. The other region lies dorsomedially, migrates
ventrally to cells that form the dermatome, and forms the myotome. Patterns of muscle formation are under the
influence of the surrounding connective tissue in to which myoblasts migrate. In the head region, this connective
tissue is derived from neural crest cells. In cervical and occipital regions muscles differentiate from somitic
mesoderm, whereas in the body wall and limbs they originate from the somatic mesoderm. By the end of the fifth week
prospective muscle cells are collected into two parts: a small dorsal portion, the epimere, and a larger
ventral part called the hypomere.1 Nerves innervating segmental muscles are also divided into a
dorsal primary ramus for the epimere and a ventral primary ramus for the hypomere. These nerves remain with their
original muscle segment throughout its migration. Myoblasts of the epimere form extensor muscles of the vertebral
column, and those of the hypomere is give rise to the muscles of the limbs and body wall. The first indication of
limb musculature is observed in the seventh week of development as a condensation of mesenchyme near the base of the
limb buds. This mesenchyme is derived from dorsolateral cells of the somites that migrate into the limb bud to form
the muscles. This connective tissue dictates the pattern of muscle formation and is derived from somatic mesoderm,
which also gives rise to the bones of the limb.1
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With elongation of the limb buds the muscles tissue splits into flexor and extensor components. The upper limb
bud lies opposite the lower five cervical and upper two thoracic segments. The lower limb buds lie opposite the lower
four lumbar and upper two sacral segments. As soon as the buds form, ventral primary rami from the appropriate spinal
nerves penetrate into the mesenchyme (Figure 2–12). At first, each ventral ramus enters with isolated dorsal and
ventral branches, but soon these branches unite to form large dorsal and ventral nerves. Thus, in the upper
extremity, the radial nerve supplies all the extensor musculature and is formed by a combination of dorsal segmental
branches. The ulnar and median nerves, which supply all the flexor muscles, are formed by a combination of the
ventral branches1 (Figure 2–13). Immediately after the nerves have entered the limb buds they establish
contact with the differentiating mesoderm condensations. This early contact is a prerequisite for their complete
functional differentiation. Spinal nerves therefore play an important role in differentiation and motor innervation
of the limb musculature, as well as providing sensory innervation for the dermatomes. Although the original
dermatomal pattern changes with growth of the extremities, an orderly sequence can still be recognized in the adult.
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Central Nervous System
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The central nervous system (CNS) originates in the ectoderm and appears as the neural plate at the
middle of the third week1 (Figure 2–14). After the edges of the plate fold, the neural folds
approach each other in the midline to fuse, forming the neural tube. The CNS then forms as a tubular
structure with a broad cephalic portion (the brain) and a long caudal portion (the spinal cord). A basal plate,
containing the motor neurons, and an alar plate, containing the sensory neurons, characterize the spinal cord, which
forms the caudal end of the CNS.
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The walls of the recently closed neural tube consist of neuroepithelial cells. These cells give rise to another
type of cell, the neuroblasts, which are primitive nerve cells. They form a mantle layer around the
neuroepithelial layer. This mantle layer later forms the gray matter of the spinal cord. The outermost layer of the
spinal cord, called the marginal layer, contains nerve fibers emerging from neuroblasts in the mantle layer.
As a result of myelination, this layer takes on a white appearance and is called the white matter of the spinal
cord.1 As a result of continuous addition of neuroblasts to the mantle layer, each side of the neural tube
shows ventral and dorsal thickening. The ventral thickening—the basal plates—contains ventral motor horn cells.
The dorsal thickening—the alar plates—forms the sensory areas. A group of neurons accumulate between these two
areas, forming a small intermediate horn, which contains neurons of the sympathetic portion of the autonomic nervous
system and is present only at thoracic and upper lumbar levels of the spinal cord1 (Figure 2–15).
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Motor nerve fibers begin to appear in the fourth week, arising from nerve cells in the basal plates of the
spinal cord.4 They collect into bundles known as a ventral nerve roots. Likewise dorsal nerve roots form as
collections of fibers originating from cells in dorsal root ganglia. Central processes from these ganglia form
processes that grow into the spinal cord opposite the dorsal horns, and distal processes join the ventral nerve roots
to form a spinal nerve. Spinal nerves divide into dorsal and ventral primary rami. Dorsal rami innervate dorsal axial
musculature, vertebral joints, and the skin of the back. Ventral primary rami innervate the limbs and ventral body
wall and form the major nerve plexuses.1
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In the third month of development, the spinal cord extends the entire length of the embryo, and spinal nerves
pass through the intervertebral foramina at their level of origin. With increasing age, the vertebral column and dura
lengthen more rapidly than the neural tube, resulting in the terminal end of the spinal cord gradually shifting to a
higher level. At birth, this level is at the third lumbar vertebra. In the adult the spinal cord terminates at the
level of L2 to L3, whereas the dural sac and subarachnoid space extends to S2. As a result of this disproportionate
growth, spinal nerves run obliquely from their segment of origin in the spinal
cord to the corresponding level of the vertebral column. Below L2 to L3 a thread-like extension of the pia mater forms
the filum terminale, which is attached to the periosteum of the first coccygeal vertebra and marks the tract of regression of the spinal
cord.1
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The brain consists originally of three vesicles: the rhombencephalon (hindbrain),
mesencephalon (midbrain), and prosencephalon (forebrain). The rhombencephalon will ultimately form
the medulla oblongata, pons, and cerebellum. The mesencephalon resembles the spinal cord with its basal and alar
plates. It will contain the anterior and posterior colliculi, forming the relay stations for visual and auditory
reflex centers. The prosencephalon will ultimately give rise to the thalamus and hypothalamus as well as the cerebral
hemispheres.1
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Autonomic Nervous System
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Functionally the autonomic nervous system can be divided into two parts: a sympathetic portion in the
thoracolumbar region, and a parasympathetic portion in the cephalic and sacral regions. Both components of the
autonomic nervous system consist of two tiers of neurons: pre- and postganglionic (Figure 2–16).
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Sympathetic Nervous System
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Preganglionic neurons of the sympathetic nervous system arise from the intermediate horn of the gray matter in
the spinal cord.3 At levels from T1 to L2 their myelinated axons grow from the cord through the
ventral roots, paralleling the motor axons that supply the skeletal musculature. Shortly after the dorsal and ventral
roots of the spinal nerve join, the preganglionic sympathetic axons, derived from the neuroepithelium of the neural
tube, leave the spinal nerve via a white communicating ramus. They soon enter one of a series of sympathetic
ganglia to synapse with neural crest-derived postganglionic neurons. The sympathetic ganglia, the bulk of which are
organized as two chains running ventrolateral to the vertebral bodies, are laid down by neural crest cells that
migrate from the closing neural tube along a special pathway. Once the migrating sympathetic neuroblasts have reached
the site at which the sympathetic chain ganglia form, they spread both cranially and caudally until the extent of the
chains approximates that seen in the adult. Some of the sympathetic neuroblasts migrate farther ventrally than the
level of the chain ganglion to form a variety of other collateral ganglia. The adrenal medulla can be broadly viewed
as a highly modified sympathetic ganglion. The outgrowing preganglionic sympathetic neurons either terminate within
the chain ganglia or pass through on their way to more distant sympathetic ganglia to form synapses with the cell
bodies of the second-order, or postganglionic, sympathetic neuroblasts. Axons of some postganglionic neuroblasts,
which are unmyelinated, leave the chain ganglion as a parallel group and reenter the nearest spinal nerve through the
gray communicating ramus. Once in the spinal nerve, these axons continue to grow until they reach their
peripheral targets.
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During the fifth week of development cells originating in the neural crest of the thoracic region migrate on each
side of the spinal cord toward the region immediately behind the dorsal aorta.1 Here they form a bilateral
chain of segmentally arranged sympathetic ganglia interconnected by longitudinal nerve fibers. Together they form the
sympathetic chains on each side of the vertebral column. From their position in the thorax neuroblasts migrate toward
the cervical and lumbosacral regions, extending the sympathetic chains to their full length. Some sympathetic
neuroblasts migrate in front of the aorta to form preaortic ganglia such as the celiac and mesenteric ganglia. Other
sympathetic cells migrate to the heart, lungs, and gastrointestinal tract, where they give rise to sympathetic organ
plexuses. Once the sympathetic chains have been established, nerve fibers originating in the intermediate horn of the
thoracolumbar segments of the spinal cord penetrate the ganglia of the chain. They are known as preganglionic fibers,
have a myelin sheath, and stimulate sympathetic ganglion cells. Passing from spinal nerves to the sympathetic
ganglia, they form the white communicating rami. Axons of the sympathetic ganglion cells, the postganglionic
fibers, have no myelin sheath. They either pass to other levels of the sympathetic chain or extend to the heart,
lungs, and intestinal tract. Other fibers, the gray communicating rami, which are found at all levels of the spinal
cord, pass from the sympathetic chain to spinal nerves and from there to peripheral blood vessels, hair, and sweat
glands.
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Parasympathetic Nervous System
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Neurons in the brainstem and the sacral region of the spinal cord give rise to preganglionic parasympathetic
fibers.1 Although also organized on a preganglionic and postganglionic basis, the parasympathetic nervous
system has a distribution quite different from that of the sympathetic system. Like those of the sympathetic nervous
system preganglionic parasympathetic neurons originate in the intermediate column of the CNS. However, the levels of
origin of these neuroblasts are the mid- and hindbrain and in the second to fourth sacral segments of the developing
spinal cord. Axons from these preganglionic neuroblasts grow long distances before they meet the neural crest-derived
postganglionic neurons. These are typically embedded in small, scattered ganglia or plexuses in the walls of the
organs they innervate.