Embryology

By admin On Jun 22, 2024

Ovid: Pediatrics

Editors: Tornetta, Paul; Einhorn, Thomas A.; Cramer, Kathryn E.; Scherl, Susan A.

Title: Pediatrics, 1st Edition

> Table of Contents > Section III: – Specialty Clinics > 31 – Embryology

Embryology

William A. Phillips

Susan A. Scherl

Knowledge of basic embryology, particularly that of the
musculoskeletal and nervous systems, is necessary in the practice of
pediatric orthopaedics. Many congenital pediatric orthopaedic
conditions are a direct result of problems in early fetal development.
The birth of a fully formed child 9 months after conception is the
culmination of an intricate series of interactions exquisitely
choreographed by the expression of many genes at different times and
places, beginning with the fertilized ovum. The events of greatest
interest to orthopaedists—the development of the musculoskeletal
system—occur primarily during the embryonic period, that is, the third
through eighth weeks after conception.

Ultimate control of embryonic development is through the
expression of the genes contained on the chromosomes. Some of the
mechanisms used in development include cell proliferation, cell
differentiation, cell migration, and cell death. These cellular events
occur not only within cells but also take place as interactions between
adjacent cells and tissues. The location of cells in the embryo and
their interactions with their local environment play a major role in
development. Cells can express genes that up- or down-regulate the
expression of other genes. This can occur by direct cell-to-cell
contact or by messenger molecules.

DEFINITIONS

Zygote: a fertilized egg and sperm
Morula: a solid ball of cells formed by division of the zygote
Blastocyst: the morula develops a fluid-filled cyst, and becomes a blastocyst
Germ layers: the three germ layers—ectoderm, mesoderm, and endoderm—give rise to all the structures of the embryo.
Ectoderm:
- □ Central nervous system
- □ Peripheral nervous system
- □ Sensory epithelia of eye, ear, and nose
- □ Epidermis, hair, and nails
- □ Mammary glands
- □ Pituitary gland
- □ Tooth enamel
- □ Neural crest cells
  - □ Spinal, cranial, and autonomic ganglia
  - □ Ensheathing cells of the peripheral nervous system
  - □ Pigment cells of the dermis
  - □ Tissues of branchial arch origin
  - □ Adrenal medulla
  - □ Leptomeninges
Mesoderm:
- □ Cartilage, bone, and connective tissue
- □ Smooth and striated muscle
- □ Heart
- □ Blood and lymph vessels and cells
- □ Gonads
- □ Pericardium, pleura, and peritoneum
- □ Adrenal cortex
- □ Spleen
Endoderm:
- □ Gastrointestinal, respiratory, genitourinary, and auditory epithelium
- □ Tonsils
- □ Thyroid and parathyroids
- □ Thymus and pancreas
- □ Liver
Mesenchyme: mesodermal embryonic connective tissue
- □ Can differentiate into fibroblasts, chondroblasts, or osteoblasts
Intramembranous ossification: direct transformation of mesenchyme into bone
- □ Mesenchymal cells condense and differentiate into osteoblasts, which lay down osteoid to become mineralized into bone.
- □ Occurs in the skull and face
Endochondral ossification: ossification of a preexisting cartilaginous bone precursor (anlage)
- □ A primary ossification center forms in the diaphyseal region of the anlage, and a secondary center forms in the epiphysis.
- □ Mesenchymal cells condense and
  differentiate into chondroblasts, which secrete collagen and ground
  substance to form the extracellular matrix.
- □ Cartilage begins to appear in the fifth week.
- □ A primary ossification center forms in
  the diaphyseal region of the anlage by week 12, and a secondary center
  forms in the epiphysis, at various times after birth, depending on the
  bone.
- □ Occurs in long bones.
Notochord: embryonic structure around which the vertebral column develops
- □ Also induces the overlying ectoderm to form the neural plate, the precursor to the central nervous system
Neural tube: the neural plate invaginates centrally to form the neural groove, bounded on either side by the neural folds
- □ The folds fuse to form the neural tube.
- □ The cranial end of the neural tube
  becomes the brain, the remainder becomes the spinal cord, and the lumen
  becomes the ventricles of the brain and central canal of the spinal
  cord (Fig. 31-1).
- □ The neural tube is induced to form different regions along its length by retinoic acid.
- □ Retinoids activate genes in the Hox (homeobox) family.
- □ Inhibition of bone morphogenic proteins also appears to play an important role in this process.
Somites: paired cuboidal bodies derived from the mesoderm running paraxially alongside the neural tube
- □ Give rise to the axial skeleton, trunk musculature, and dermis
- □ Each somite differentiates into a ventromedial sclerotome, which will form the vertebrae and ribs, and a dorsolateral dermomyotome, which separates into the myotome, which will form the muscles and the dermatome, which will form the skin.
- □ Some of the molecular events associated with somite formation include the expression of Notch pathway and Hox genes.

Figure 31-1 Development of the spinal cord. (A-C) Formation of the neural tube and neural crest in early somite embryos. (D) Cellular differentiation within the cord. (E)
Development of cell columns in the alar and basal laminae shown on one
side for a segment that innervates the limbs and on the other for a
segment that contains the visceral efferent column. (From Rosse C,
Gaddum-Rosse P. The vertebral canal, spinal cord, spinal nerves, and
segmental innervation. In: Hollinshead’s textbook of anatomy, 5th ed.
Philadelphia: Lippincott-Raven, 1997:152.)

EARLY FETAL DEVELOPMENT

Day 1: fertilization, formation of zygote
Day 2: morula stage
Day 4: blastocyst stage
Day 6 to 10: uterine implantation
Day 11: placental circulation established
Day 15: first period missed
Day 16 to 18: notochord and neural plate form
Day 20: somites form

P.341
- □ Early in the third week, formation of the primitive streak orients the embryo in all three planes—longitudinal (cranial-caudal), sagittal (dorsal-ventral), and coronal (left-right).
- □ Cells migrating from the deep surface
  of the primitive streak move between the dorsally placed ectoderm and
  ventrally placed endoderm to become the mesoderm.
Week 4: neural tube forms, heart beats, arm and leg buds appear
Week 5: mouth, eyes, and hands develop
Week 6: feet and fingers develop
Week 7: toes develop

In general, if there is a congenital abnormality in one
organ system, it is imperative to rule out abnormalities in all organ
systems developing at the same time. For example, since the elements of
the spine and heart develop simultaneously, children with congenital
scoliosis must be evaluated for heart defects.

ARTICULAR AND SKELETAL DEVELOPMENT

The skeleton derives from mesodermal mesenchyme.
Regulators of bone development include bone morphogenic proteins (BMP), transforming growth factor-β (TGF-β), and homeobox (Hox) genes.
In long bones, the mesenchyme develops into a cartilaginous anlage, which undergoes endochondral ossification to form bone.
In the skull, the mesenchyme transforms directly into bone through intramembranous ossification.
The vertebrae and ribs develop from the fusion of the upper and lower halves of adjacent somites.
Joints develop from the interzonal
mesenchyme between the bony anlage. Interzonal mesenchyme can
differentiate into fibrous or cartilaginous tissue to form a joint, and
cavitates to form synovial spaces.
Malformations of the axial skeleton:
- □ Klippel-Feil syndrome: failure of segmentation of cervical vertebrae
- □ Spina bifida occulta: failure of fusion of the halves of the vertebral arch
- □ Hemivertebrae: failure of appearance of
  one of the two ossification centers forming a vertebral body, leading
  to failure of formation of half of the vertebra
- □ Rachischisis: failure of fusion of the neural folds
- □ Achondroplasia: disruption of endochondral ossification.

LIMB DEVELOPMENT

Limb buds appear at the end of the fourth week of gestation.
The upper limb buds develop slightly ahead of the lower.
The limb buds are formed from somatic mesoderm and ectoderm.
Limb buds start forming on the ventrolateral surface of the body wall.
Mesenchymal cells in the lateral mesoderm are activated beneath a thickened band of ectoderm.
- □ This thickening is the apical ectodermal ridge (AER).
- □ The AER interacts with limb bud mesenchyme to promote growth of the limb from proximal to distal.
- □ Fibroblast growth factors are expressed in the AER.
- □ At the posterior margin of the limb bud, mesenchymal cells form the zone of polarizing activity,
  which controls limb development in the anteroposterior axis (first vs.
  fifth digit sides of limb) through the expression of the sonic hedgehog (Shh) gene.
- □ The dorsoventral axis (flexor vs. extensor sides of the limb) is determined by Wnt7 from the dorsal epidermis and engrailed-1 (EN-1) from the ventral side.
Homeobox (Hox) genes play an important role in limb development.
- □ This gene family was first described in the fruit fly (Drosophila). Hox genes are highly conserved and regulate vertebra development in a similar manner as they do in Drosophila.
- □ They code for transcription factors
  that regulate DNA transcription of other genes. In a sense, Hox genes
  are the switches by which other genes are activated during
  embryogenesis.
- □ The order of Hox
  genes along the chromosome determines the order in which they are
  expressed. Genes at the 3′ end of a sequence are expressed earlier and
  more anteriorly on the body.
At the beginning of the seventh week, the
limbs extend ventrally with the palmar surface of the hands and the
plantar surface of the feet facing each other. The thumbs and great
toes are both on the cephalad, preaxial border of their respective
limbs.
During the eighth week, the upper limbs
rotate laterally, pointing the elbows caudally. The elbows flex so the
hands meet across the chest. The forearm flexor muscles now lie on the
medial side of the arm and the extensors lie laterally. At the same
time, the lower limbs rotate medially. This places the soles of the
feet in a plantar position. The leg flexor muscles lie dorsally and the
extensors lie ventrally.
Limb development is complete by the eighth week of gestation (Fig. 31-2).
By the end of the sixth week, the rays of the hands have formed,
followed in a few days by the foot rays. By the eighth week the
mesenchyme between the rays breaks down, separating the digits. This
occurs through apoptosis (programmed cell death) and is regulated by bone morphogenic proteins.
Limb malformations are usually genetic,
but environmental and teratogenic factors have also been implicated in
some cases, and causation may be multifactorial.
Often, limb malformations are relatively
minor in and of themselves, but they may be associated with other more
serious congenital problems or syndromes.
Limb malformations:
- □ Cleft hand and foot—failure of formation of central ray
- □ Radial club hand—partial or complete
  absence of the radius. May present with thrombocytopenia (TAR
  (thrombocytopenia-absent radius] syndrome) or as part of VATER syndrome
  (vertebral anomalies, anal atresia, tracheoesophageal fistula, renal
  and radial anomalies)
- □ Brachydactyly—short fingers or toes, often inherited.
- □ Polydactyly—extra fingers or toes
  - □ Postaxial (medial on the upper extremity, lateral on the lower) polydactyly is autosomal dominant
  - □ Preaxial is rarer and more likely to be a sporadic event.
- □ Amelia—complete absence of the limbs,
  caused by early suppression of limb development. Thalidomide, an
  anti-nausea drug used during pregnancies between 1957 and 1962, can
  cause amelia.
- □ Meromelia—partial absence of the limbs, caused by suppression of limb development later in gestation

Figure 31-2 (A)
Development of the bones in the free limbs in relation to the limb
axis. The bone primordium of the proximal segment is dark gray, the
preaxial bone of the intermediate segment is black, and the postaxial
bone is white. (B and C) Successive stages
of limb development from a ventral view before the limbs undergo
rotation. The position of the preaxial and postaxial bone in the upper
and lower limbs is still symmetric. (From Rosse C, Gaddum-Rosse P.
Basic structural plan of the limbs. In: Hollinshead’s textbook of
anatomy, 5th ed. Philadelphia: Lippincott-Raven, 1997:183.)

MUSCLE DEVELOPMENT

Most skeletal muscle is derived from the ventral dermomyotomal portion of the somites.
Head and neck muscle is derived from branchial arch mesoderm.
Limb muscles develop from mesenchyme derived from somatic mesoderm.
Muscle development is initiated by Shh from the notochord and Wnts from the neural tube, inducing Pax-3 and Myf-5 in the somites.
Pax-3 in turn regulates c-met expression, which directs migration of the myogenic precursor cells into the limb bud.
In each limb the cells condense into two masses, dorsal and ventral to the axial mesenchyme.
- □ The dorsal muscle mass becomes most of
  the extensors and supinators of the upper limb and the extensors and
  abductors of the lower limb.
- □ The ventral muscle mass becomes the flexors and pronators of the upper limb and the flexors and adductors of the lower limb.
Cardiac and smooth muscles develop from splanchnic mesoderm.
There is wide developmental variation in musculature.
Absences or variations is size, shape, and position of muscles is common, and generally not of clinical significance.
The most common significant congenital
muscle lesion is torticollis, an intrauterine scarring and fibrosis of
the sternocleidomastoid muscle, which causes a fixed rotation and
tilting of the head.

NERVOUS SYSTEM DEVELOPMENT

In the peripheral nervous system, all sensory cells are derived from the neural crest.
- □ Neural crest cells in the region of the brain form the sensory ganglia of cranial nerves V and VII through X.
- □ The autonomic ganglia are also derived from the neural crest.
- □ Motor nerve fibers develop from cells in the fetal spinal cord.
- □ Growing limb buds are supplied with segmental motor and sensory innervation, which grow into the mesenchyme.
- □ The central nervous system derives from ectodermal tissue on the dorsal aspect of the fetus known as the neural plate.
- □ The neural plate infolds to form the neural groove and neural folds.
- □ The neural folds fuse to form the neural tube.
- □ The neural crest is a layer of cells between the neural tube and the surface ectoderm.
- □ The cranial end of the neural tube
  becomes the brain and the remainder becomes the spinal cord, while the
  lumen becomes the ventricles of the brain and central canal of the
  spinal cord.
Problems during this process are common,
and lead to various congenital brain and spinal cord abnormalities,
including spina bifida and anencephaly.
Since this process occurs very early in
gestation (at about 3 weeks), typically before a woman knows she is
pregnant, preventive measures such as adequate (400 to 800 µg) intake
of folate should begin prior to attempts at conception.