EARLY EMBRYOLOGY: SOMITE STAGE AND LIMB BUDS
* Week 1-2: formation of zygote, implantation and formation of bilaminar embryo.
* Weeks 3-8: Embryological period .
* Weeks 9-38: Fetal period .
DEVELOPMENT OF THE SOMITES (week 3)
The intraembryonic mesoderm on each side of the forming notochord and neural tube thickens to form a longitudinal column of paraxial mesoderm. By the end of the 3rd week, the paraxial mesoderm divides into paired bodies called somites, located bilaterally of the neural tube .
* The somites give rise to the axial skeleton (vertebrae, ribs), associated musculature and adjacent dermis of skin.
* The first pair of somites develop a short distance posterior to the cranial end of the notochord, and the rest of the somites form caudally. Around 38 pairs of somites form during the somite period of development, from days 20 to 30. The final number is 42 to 44 pairs. The somites may be used as a criterion to determine the age of the embryo .
* A cavity, the mycocoele, forms within each somite but disappears.
* Each somite becomes differentiated into ventromedial sclerotome (for vertebrae and ribs), myotome (muscles) and dermatome (skin; .
* At the beginning of the 4th week, the somites (4) are well formed and the neural tube is also formed but it is opened at the rostral and caudal neuropores .
* Upper limb buds become recognizable during week 4 and the lower limb buds become present by the end of week 4 (day 28 ). The patterning of the limb development is regulated by Homeobox-containing (Hox) genes.
* The upper limb buds appear low on the embryo due to the dominant development of the head and neck.
* The upper limb buds form opposite the caudal cervical segments and lower limb buds form opposite the lumbar and upper sacral segments.
Each limb bud consists of a mass of mesenchyme derived from the somatic mesoderm, covered by a layer of ectoderm. At the tip of each limb bud, ectodermal cells form an apical ectodermal ridge, which promotes growth and development of the limbs in the proximo-distal axis . Fibroblast growth factors and T-box genes (tbx-4 and tbx-5) from the apical ectodermal ridge activate the mesenchymal cells at the posterior margin of the limb bud (the zone of polarizing activity). This causes expression of the Sonic Hedgehog gene, which controls the patterning of the limb along the anterior-posterior axis. Expression of Wnt7 from the dorsal epidermis of the limb bud and engrailed-1 (EN-1) from the ventral aspect specifies the dorsal-ventral axis
* Bones appear during week 5 as mesenchymal condensations in the limb buds .
* Upper limbs show regional differentiation with developing hand plates
* Mesenchymal models of the bones in the limbs undergo chondrification to form hyaline cartilage.
* The clavicle develops by intramembranous ossification and later develops articular cartilages.
* The cartilage models form sooner in the upper limb than in the lower limb and in a proximodistal sequence.
Further differentiation of the limb buds during week 6
* Identifiable elbow and wrists regions are formed.
* Hand plates develop ridges, called digital rays and these will become the future thumb and fingers. At the tip of each digital ray is a portion of the apical ectodermal ridge. It induces development of the mesenchyme into the primordia of bones. Areas between the rays contain loose mesenchyme.
* Development of the lower limb buds is always slower by a few days.
* Loose mesenchyme between the digital rays break down and notches appear between the digital rays in the hand plates.
* Digital rays form in the foot plate.
* Ossification in the long bones begin by the end of the embryonic period (week 7). The primary centers are in the diaphyses
* Limb muscles are formed by myogenic precursor cells that migrate into the limb buds and differentiate into myoblasts. They are derived from the dorsolateral muscle-forming region of the somites, an area which expresses the muscle-specific genes MyoD and myf-5. Expression of MyoD results from the influence of activating Wnt proteins and inhibitory BMP-4 protein. The myoblasts form a muscle mass which divides into a dorsal (extensor) and ventral (flexor) compartments.
Limb rotation begins
* Originally, the flexor aspect of the limbs is ventral and the extensor aspect is dorsal; the preaxial border is cranial and the postaxial border is caudal in direction.
* The upper limbs rotate 90 degrees on their longitudinal axis. Elbows point posteriorly and extensor muscles now lie lateral and posterior.
* The lower limbs rotate 90 degrees in the opposite direction of rotation of the upper limbs and the knees face anteriorly. The extensor muscles now lie anteriorly.
* The radius in the forearm is homologous to the tibia in the leg, and the ulna is homologous to the fibula.
* Muscles of the limb shift their position during development because of the lateral rotation of the upper limb and medial rotation of the lower limb.
* Muscles forming on the dorsal side of the long bones give rise to extensor and supinator muscles of the upper limbs and extensor and abductor muscles of the lower limb. They are innervated by the dorsal branches of the ventral primary rami.
* Muscles forming on the ventral side of the long bones become flexor and pronator muscles of the upper limb and flexor and adductor muscles of the lower limb. They are innervated by the ventral branches of the ventral primary rami.
Week 8 (Last week of embryonic life;
At the beginning of week 8,
* The digits of the hand are short and webbed.
* Notches develop between the digital rays of the feet.
At the end of week 8, there are distinct regions in the limbs, with long fingers and distinct toes.
* The fetus has short legs and small thighs at the beginning of week 9.
* By the end of week 12, the upper limbs have reached their final relative length but the lower limbs have not.
* Primary ossification centers are present in all long bones
* Order of ossification: Clavicle, femora, etc…
* Secondary ossification centers appear in the epiphyses . The first ones to appear are in the distal end of the femur and the proximal end of the tibia, at the knee joint.
* The epiphyseal cartilage plate intervenes between the diaphysis and epiphysis. When it is replaced around age 25, growth of the bones ends.
A dermatome is the area of skin innervated by a single spinal nerve and its dorsal root ganglion .
Development of the innervation of the limbs
* Peripheral nerves grow from the brachial and lumbar plexuses into the mesenchyme of the limb buds during week 5.
* The distribution is segmental, supplying both dorsal and ventral aspects.
* As the limbs elongate, the cutaneous distribution follows and an orderly sequence can still be seen in the adult.
* There is no overlap across the axial line.
Development of the blood supply to the limbs
Limb buds are supplied by branches of the intersegmental arteries arising from the aorta ,
Initially, a primary axial artery and its branches supply the limb bud and a peripheral marginal sinus drains it.
In the upper limb,
* The primary axial artery becomes the brachial artery in the arm and the common interosseous artery in the forearm.
o The terminal branches of the brachial artery are the radial and ulnar arteries.
o The terminal branches of the common interosseous arteries are the anterior and posterior interosseous arteries.
* With the formation of the digits the marginal sinus breaks up into the dorsal venous arch. The final pattern of basilic and cephalic veins and their tributaries then arises.
In the lower limb,
* The primary axial artery will form the profunda femoris artery in the thigh, and the anterior and posterior tibial arteries in the leg.
Embryology of the spine and spinal cord
The AXIAL SKELETON is formed by the :
* VERTEBRAL COLUMN
* 12 PAIRS OF RIBS
Development of the vertebral column
Precartilaginous (mesenchymal) stage
During week 4, mesenchymal cells from the sclerotome of the somites are found in 3 main areas
* around the notochord,
* surrounding the neural tube,
* in the body wall.
1. Around the notochord
Each sclerotome consists of loosely packed cells cranially and densely packed cells caudally
o Some densely packed cells move cranially and form the intervertebral disc. Peripheral nerves will form close to the intervertebral discs.
o The remaining densely packed cells fuse with the loosely arranged cells of the adjacent caudal sclerotome and form the mesenchymal centrum of the vertebra.
* Each centrum thus develops from 2 adjacent sclerotomes and becomes an intersegmental structure
o Intersegmental arteries will come to lie on each side of the vertebral bodies. In the thorax, the dorsal intersegmental arteries become the intercostal arteries.
The notochord degenerates and disappears where it is surrounded by the vertebral body.
o Between the vertebrae, the notochord expands to form the nucleus pulposus
o The nucleus pulposus is later surrounded by the circular fibers of the anulus fibrosus.
o The nucleus pulposus and anulus fibrosus form the intervertebral disc.
o Remnants of the notochord may persist and give rise to a chordoma. This slow-growing neoplasm occurs most frequently at the base of the skull and in the lumbosacral region (arrows in scans below) .
2. Surrounding the neural tube
These mesenchymal cells form the vertebral arch
3. In the body wall
These mesenchymal cells form the costal processes which develop into ribs in the thoracic region.
The cartilaginous stage
During week 6, chondrification centers appear in each mesenchymal vertebra
o The 2 centers in each centrum fuse at the end of the embryonic period to form a cartilaginous centrum.
o At the same time, the centers in the vertebral arches fuse with each other and with the centrum.
o The spinous and transverse processes develop from extensions of chondrification centers in the vertebral arch.
Chondrification spreads until a cartilaginous vertebral column is formed.
The bony stage
Ossification of the typical vertebrae begins during the embryonic period and ends by year 25 of life.
2 (ventral and dorsal) primary ossification centers for the centrum fuse to form one.
3 primary ossification centers at the end of the embryonic period
o in the centrum.
o in each half of the vertebral arch (Ossification is evident around week 8).
At birth, each vertebra consists of 3 bony parts connected by cartilage
The halves of the vertebral arch fuse during years 3-5.
The laminae of the arch first unite in the lumbar region and the progression moves cranially.
The vertebral arch articulates with the centrum at cartilaginous neurocentral joints .
These articulations permit the vertebral arches to grow as the spinal cord enlarges.
The neurocentral joints disappear when the vertebral arch fuses with the centrum during years 3-6.
5 secondary ossification centers appear
o tip of the spinous process.
o tip for each transverse process.
o 2 rim (annular) epiphyses: 1 superior and 1 inferior for the vertebral body.
The vertebral body is a composite of the superior and inferior annular epiphyses and the mass of bone between them. It includes the centrum, parts of the vertebral arch and the facets for the heads of the ribs.
All secondary centers unite with the rest of the vertebra around year 25.
Ossification of atypical vertebrae
Exceptions to the typical ossification of vertebrae occur in C1, C2, C7, lumbar vertebrae, sacrum and coccyx.
o 95% of the population has 7C, 12 T, 5 L and 5 S vertebrae.
o 3% have 1 or 2 more vertebrae.
o 2% have 1 less.
Examine the entire vertebral column because an apparent extra or absent vertebra in one segment may be compensated by an absent or extra vertebra in an adjacent segment (ex: 11T and 6 L vertebrae).
Development of the spinal cord
The nervous system develops from an area of embryonic ectoderm called the neural plate which appears during week 3
The underlying notochord and adjacent mesoderm induce the formation of the neural plate. The neural tube and the neural crest differentiate from the neural plate.
* The neural tube gives rise to the central nervous system (brain and spinal cord;
* The neural crest gives rise to the peripheral nervous system (cranial, peripheral, autonomic ganglia and nerves) and Schwann cells, pigment cells, odontoblasts, meninges, and bones and muscles of the head
Central nervous system
* Formation of the neural tube begins during the early part of week 4 (22-23 days) in the region of the 4th to 6th pairs of somites (future cervical region of the spinal cord;
* At this stage ,the cranial 2/3 of the neural plate and neural tube down to somites #4 represent the brain and the caudal 1/3 of the neural tube and plate represent the spinal cord.
* Neural folds fuse and the neural tube is temporarily open at both ends, communicating freely with the amniotic cavity.
* The rostral neuropore closes around day 25 and caudal neuropore on day 27.
* Walls of the neural tube thicken to form the brain and spinal cord.
* The lumen of the neural tube is converted to the ventricular system of the brain and the central canal of the spinal cord.
The spinal cord is formed from the neural tube caudal to somites 4.
* The central canal is formed by week 9 or 10
* Pseudostratified, columnar neuroepithelium in the walls constitute the ventricular zone (ependymal layer) and give rise to all neurons and macroglial cells (astroglia and oligodendroglia) in the spinal cord
* The outer parts of the neuroepithelial cells differentiate into a marginal zone which will give rise to the white matter of the spinal cord as axons grow into it from neurons in the spinal cord, spinal ganglia and brain.
* Neuroepithelial cells in the ventricular zone differentiate into neuroblasts and form an intermediate zone between the ventricular and marginal zones. They will give rise to neurons.
* Glioblasts (spongioblasts) differentiate from neuroepithelial cells after neuroblast formation has stopped. They migrate from the ventricular zone into the intermediate and marginal zones. Some become astroblasts and then astroglia (astrocytes). Others become oligodendroblasts and then oligodendroglia (oligodendrocytes). The remaining neuroepithelial cells differentiate into ependymal cells lining the central canal of the spinal cord
* Microglia are derived from the mesenchymal cells. They invade the nervous system late in the fetal period after penetration from blood vessels.
Proliferation and differentiation of the neuroepithelial cells in the developing spinal cord produce thick walls and thin roof and floor plates. A shallow longitudinal sulcus limitans appears in the lateral walls of the spinal cord and separates the dorsal alar plate from the ventral basal plate
* Alar plates: cells form the dorsal horns and will have afferent functions.
* Basal plates: cells form the ventral and lateral horns and will have efferent functions. Axons grow out of the spinal cord to form the ventral roots.
* The dorsal root ganglia are formed from the neural crest cells. Their axons enter the spinal cord and form the dorsal roots.
Mesenchyme surrounding the neural tube condenses to form the primitive meninx.
* The outer layer thickens to form the dura mater.
* The inner layer remains thin and forms the pia-arachnoid.
Positional changes of the developing spinal cord
In the embryo, the spinal cord extends the entire length of the vertebral canal and the spinal nerves pass through the intervertebral foramina near their levels of origin.
This relationship does not persist because the spine and the dura mater grow more rapidly than the spinal cord. The caudal end of the spinal cord comes to lie at relatively higher levels.
Positional changes of the developing spinal cord
* At month 6 of gestation, the end of the spinal cord lies at the level of S1.
* In the newborn infant, it lies at L 3
* In the adult, it lies at L 2-3. Lumbar and sacral spinal nerve roots run obliquely from the spinal cord to their corresponding intervertebral foramina inferiorly.
* are mostly due to the defective closure of the caudal neuropore at the end of week 4. The defects will involve the tissue overlying the spinal cord (meninges, vertebral arch, dorsal muscles and skin).
* involving the spinal cord and vertebral arches are called spina bifida (nonfusion of the vertebral arches; The Developing Human, 8th ed., p. 391)
Spina bifida occulta
* is a defect in the vertebral arch (neural arch) resulting from failure of the halves of the vertebral arch to grow normally and fuse in the median plane.
* occurs at L 5 or S 1 vertebra in about 10% of the population.
* may only be evident as a small dimple with a tuft of hair.
* produces no clinical symptoms although a small percentage may have significant defects of the underlying spinal cord and spinal roots.
Spinal dermal sinus
* representing the area of closure of the caudal neuropore at the end of week 4,
* It is the last place of separation between the ectoderm and the neural tube.
* The dimple may be connected by a fibrous cord with the dura mater.
Intramedullary dermoids are tumors arising from surface ectodermal cells incorporated into the neural tube during closure of the caudal neuropore.
Spina bifida cystica
* is a protrusion of the spinal cord and/or meninges through the defective neural arch.
* is present in 1/1000 births.
* may result in loss of sensation in corresponding dermatome, complete or partial skeletal muscle paralysis, sphincter paralysis (with lumbar meningomyeloceles) and saddle anesthesia.
* with meningocele: only meninges and cerebrospinal fluid in the sac.
* with meningomyelocele spinal cord and nerve roots included with meninges and CSF in the sac, covered by skin or thin membrane. There are marked neurological deficits inferior to the sac, due to incorporation of the neural tissue into the wall of the sac (This usually occurs in the lumbar region and may be associated with craniolacunia or defective calvarium).
* with myeloschisis (with myelocele: open spinal cord due to failure of neural folds to fuse. The spinal cord in this area is a flattened mass.
* cystica and/or meroanencephaly (absence of part of the brain; is suspected in utero when there is a high-level of alpha-fetoprotein in the amniotic fluid or in the maternal blood serum.
o Amniocentesis or ultrasound should be performed at about week 10 when the vertebral column becomes visible.
The lower respiratory system (from the pharynx down)
* develops during week 4 (26-27 days)
* starts as a median laryngotracheal groove in the caudoventral wall of the primitive pharynx.
* The endoderm lining the groove gives rise to the epithelium and glands of the larynx, trachea, bronchi and the pulmonary epithelium.
* Connective tissue, cartilage and smooth muscle of these structures develop from the splanchnic mesenchyme surrounding the foregut.
The laryngotracheal groove deepens into a diverticulum ventrally which enlarges distally into a lung bud . The diverticulum becomes separated from the primitive pharynx by longitudinal trachoesophageal folds which fuse to form the trachoesophageal septum, dividing the foregut into the ventral laryngotracheal tube and the dorsal esophagus.
A fistula may exist connecting trachea and esophagus and resulting in abnormal communication between the 2.
* This is usually associated with superior esophageal atresia. In a newborn infant, this is associated with coughing and choking upon swallowing. Gastric contents may reflux into the trachea and lungs resulting in pneumonia or pneumonitis (inflammation of the lungs).
* An excess of amniotic fluid (polyhydramnios) is associated with esophageal atresia and trachoesophageal fistula because amniotic fluid may not pass to the stomach and intestines for absorption and transfer via the placenta for disposal.
The lung bud develops into 2 endodermal bronchial buds which grow into the pericardioperitoneal cavities, the primordia of the pleural cavities.
* Early in week 5, each bronchial bud enlarges into the primordium of a primary bronchus. The right one is slightly larger than the left and is oriented more vertically .
* The primary bronchi subsequently divide into secondary bronchi and then into the tertiary bronchi by week 7.
* By week 24, they divide another 14 times and the respiratory bronchioles have developed.
* They will divide an additional 7 more times before birth.
* As the bronchi develop, the surrounding mesenchyme synthesizes the surrounding cartilages, smooth muscle, connective tissue and capillaries.
* The lungs acquire a layer of visceral pleura from the splanchnic mesenchyme.
* The thoracic body wall becomes lined by a layer of parietal pleura derived from the somatic mesoderm.
1) Pseudoglandular period (5-17 weeks)
By week 17 all major elements of the lungs have formed except for those involved with gas exchange. The lungs look like an endocrine organ. No respiration is possible!
2) Canalicular period (16-25 weeks)
The lumen of the bronchi and terminal bronchioles become larger and the lungs become vascularized. By week 24, respiratory bronchioles have developed and respiration becomes possible, although the chances of survival are slim.
3) Terminal sac period (24 weeks to birth)
* More terminal sacs develop and capillaries enter into close relationship with them. They are lined with Type 1 alveolar cells or pneumocytes.
* Type II pneumocytes secrete surfactant counteracting the surface tension forces and facilitating expansions of the terminal sacs.
Surfactant reaches adequate levels 2 weeks before birth.
Adequate pulmonary vasculature and sufficient surfactant are critical to the survival of premature infants.
4) Alveolar period (late fetal period to 8 years)
95% of the mature alveoli develop after birth. A newborn infant has only 1/6 to 1/8 of the adult number of alveoli and the lungs look denser in an x-ray.
Developing lungs at birth are half filled with amnotic fluid. The fluids in the lungs are cleared:
* through mouth and nose by pressure on the thorax during delivery.
* into the pulmonary capillaries.
* into the lymphatics and pulmonary arteries and veins.
The cardiovascular system begins to develop during week 3.
Mesenchymal cells derived from the mesoderm form endothelial tubes which join to form the primitive vascular system
HEART DEVELOPMENT (WEEK 3)
Heart develops from splanchnic mesenchyme in the cardiogenic area.
Bilateral cardiogenic cords
* are formed from the mesenchyme
* become canalized
* and form the paired endocardial heart tubes .These fuse into a single heart tube forming the primitive heart.
Surrounding mesenchyme thicken to form the myoepicardial mantle (future myocardium and epicardium) separated from the endothelial heart tube (future endocardium) by the gelatinous cardiac jelly ,
The future heart develops dilatations and constrictions resulting in 4 chambers
* sinus venosus
* primordial atrium
* bulbus cordis
The truncus arteriosus is continuous caudally with the bulbus cordis, and enlarges cranially to form the aortic sac from which the aortic arches arise .
The sinus venosus receives
* the umbilical veins from the chorion.
* the vitelline veins from the yolk sac
* the common cardinal veins from the embryo.
3 systems of paired veins drain into the primitive heart:
* the vitelline system will become the portal system;
* the cardinal veins will become the caval system;
* the umbilical system which degenerates after birth
The bulbus cordis and the ventricle grow faster and the heart bends upon itself, forming a bulboventricular loop .
The atrium and sinus venosus come to lie dorsal to the bulbus cordis, truncus arteriosus and ventricle .
At the same time, the heart invaginates into the pericardial cavity .
The dorsal mesocardium which attaches it to the dorsal wall of the pericardial cavity degenerates and forms the tranverse pericardial sinus (.
First heartbeat occurs at 21 to 22 days and originates in the muscle, forming peristalsis-like waves beginning in the sinus venosus.
By the end of week 4 coordinated contractions of the heart results in unidirectional flow:
* Blood enters the sinus venosus from the vitelline, cardinal and umbilical veins
* Blood flows into the primitive ventricle;
* Upon ventricular contraction, blood flows into the bulbus cordis and the truncus arteriosus into the aortic sac, passing into the aortic arches and branchial arches;
* Blood then passes to the dorsal aortae for distribution to the embryo, yolk sac and placenta.
The heart divides into 4-chambered heart between weeks 4 and 7.
1) Endocardial cushions form on the dorsal and ventral walls of the atrioventricular canal. At week 5, they approach each other and fuse, dividing the atrioventricular canal into right and left canals.
2) Atria are partitioned successively by the septum primum and the septum secundum . The latter is an incomplete partition and leaves a foramen ovale. The foramen ovale has a valve formed from the degeneration of the cranial portion of the septum primum.
Before birth the foramen ovale allows blood to pass from the right atrium into the left atrium; reflux is prevented by the valve .
After birth the foramen ovale normally closes by fusion of the septum primum and the septum secundum.
3) The sinus venosus develops a left horn which becomes the coronary sinus and a right horn which will be incorporated into the right atrium. The smooth part of the right atrium, the sinus venarum, is derived from the sinus venosus whereas the
muscular part, the auricle, is derived from the primitive atrium. The 2 portions are separated internally by the crista terminalis and externally by the sulcus terminalis.
4) The primitive pulmonary vein and its 4 main branches become partially incorporated into the left atrium . This results in the 4 pulmonary veins. The portion derived from the original left atrium retains a trabeculated apperance.
5) The ventricles become partitioned by a crescentic fold which is open cranially until the end of week 7 (interventricular foramen; . The interventricular septum is formed of a central membranous part and a surrounding muscular part. After closure, the right ventricle communicates with the pulmonary trunk and the left ventricle with the aorta.
6) During week 5, the bulbus cordis and the truncus arteriosus become divided by an aorticopulmonary septum into the definitive pulmonary trunk and aorta . Valves develop from proliferation of the subendocardial tissue.
The primitive atrium acts as a temporary pacemaker. But the sinus venosus soon takes over.
* The sinuatrial (SA) node develops during week 5. It is part of the sinus venosus which becomes incorporated into the right atrium.
* The atrioventricular (AV) node also develops from the cells in the wall of the sinus venosus together with cells from the atrioventricular canal region.
The critical period of development is from day 20 to day 50 after fertilization.
Improper partitioning of the heart may result in defects of the cardiac septa, of which the ventricular septal defects are most common (25% of congenital heart disease).
Membranous ventricular septal defect (most common):
* involves the oval membranous portion of the interventricular septum which fails to develop.
* is due to the failure of extensions of subendocardial tissue growing from the right side of the fused endocardial cushions and fusing with the aorticopulmonary septum and the muscular part of the interventricular septum.
Muscular septal defect:
* Perforation may appear anywhere in the muscular part of the interventricular septum (multiple defects = Swiss cheese type of ventricular septal defect) due
perhaps to excessive resorption of myocardial tissue during formation of the muscular part of the interventricular septum.
Absence of interventricular septum is rare and results in a 3-chambered heart called cor triloculare biatriatum.
The tetralogy of Fallot consists of
* pulmonary valve stenosis: the cusps of pulmonary valve are fused together to form a dome with a narrow central opening.
* ventricular septal defect
* overriding aorta
* hypertrophy of right ventricle
Cyanosis is an obvious sign but may not be present at birth.
* When the branchial arches form during week 4 and 5, they are penetrated by arteries arising from the aortic sac, which are called the aortic arches.
* During week 6 to 8 the primitive aortic arch pattern is transformed into the adult arterial arrangement of carotid, subclavian, and pulmonary arteries (The Developing Human, 8th ed., p. 321).
The lymphatic system begins to develop around week 5 (The Developing Human, 8th ed., p. 334).
* 6 primary lymph sacs develop and later become interconnected by lymph vessels;
* lymph nodules do not appear until just before and/or after birth.
* Hygroma: tumor-like mass of dilated lymphatic vessels derived from the pinched-off portion of the jugular lymph sac.
* Oxygenated blood returns from the placenta by the umbilical vein.
* Half of the blood passes through the liver whereas the other half bypasses the liver by the ductus venosus.
* Blood enters into the inferior vena cava and then the right atrium of the heart. This blood is now partially deoxygenated because it is mixed with returning blood from the lower portion of the body and the abdominal organs.
* Most of the blood in the right atrium passes through the foramen ovale into the left atrium and mixes with the blood returning from the lungs (deoxygenated).
* From the left atrium, blood passes into the left ventricle and the ascending aorta. Arteries to the heart, head and neck, and upper limbs receive well-oxygenated blood.
* A small amount of blood from the right atrium mixes with blood from the superior vena cava and coronary sinus. It passes into the right ventricle and leaves via the pulmonary trunk. Most of it passes into the ductus arteriosus into the aorta. A small amount passes into the lungs.
* 50% of the blood passes via the umbilical arteries into the placenta for reoxygenation, the rest supplies the viscera and the inferior 1/2 of the body.
After birth, the foramen ovale, ductus arteriosus, ductus venosus and umbilical vessels are no longer needed and they close
The right ventricular wall is thicker in the newborn but by the end of month 1, the left ventricular wall is thicker.
The fetal circulation is designed to carry oxygenated blood from the placenta to the fetal circulation, bypassing the lungs.
* Changes that will result in a normal adult circulation occurs during infancy.
* Defects will commonly involve a patent foramen ovale and/or patent ductus arteriosus
Development of the body cavities and the diaphragm
The Developing Human – Clinically Oriented Embryology – Moore and Persaud, 8th edition – Chapter 8
The intraembryonic coelom is the primordium of the embryonic body cavities and begins to develop near the end of week 3 . By the beginning of week 4, it is a horseshoe-shaped cavity in the cardiogenic and lateral mesoderm.
The curve of the horseshoe represents the future pericardial cavity (.) and its lateral limbs represent the future pleural and peritoneal cavities .
During folding of the embryonic disc in week 4, the lateral parts of the intraembryonic coelom are brought together on the ventral aspect of the embryo .
* When the caudal part of the ventral mesentery disappears, the right and left parts of the intraembryonic coelom merge and form the peritoneal cavity.
* As the peritoneal portions of the intraembryonic coelom come together, the splanchnic layer of the mesoderm encloses the primitive gut and suspends it from the dorsal body wall by a double-layered peritoneal membrane known as the dorsal mesentery.
Until week 7, the embryonic pericardial cavity communicates with the peritoneal cavity through paired pericadioperitoneal canals ,
During weeks 5 and 6, partitions form near the cranial and caudal ends of these canals:
* Fusion of the cranial pleuropericardial membranes with mesoderm ventral to the esophagus separates the pericardial cavity from the pleural cavities ,
* Fusion of the caudal pleuroperitoneal membranes , during formation of the diaphragm, separates the pleural cavities from the peritoneal cavity.
The diaphragm forms from ,
1) the septum transversum,
2) the pleuroperitoneal membranes,
3) the dorsal mesentery of the esophagus,
4) the body wall.
A posterolateral defect of the diaphragm results in congenital diaphragmatic hernia and is due to failure of fusion between the pleuroperitoneal membranes and other diaphragmatic components.
Embryology of the abdominal contents
The Developing Human – Clinically Oriented Embryology – Moore and Persaud, 8th edition – Chapter 11
The primitive gut forms during week 4 when the embryo folds and incorporates the dorsal part of the yolk sac
* The endoderm of the primitive gut gives rise to the epithelial lining of most of the digestive tract, biliary passages and parenchyma of liver and pancreas.
* The epithelium of the cranial and caudal ends of the digestive tract is derived from the ectoderm of the stomodeum and proctodeum (fig. 11-1), respectively.
* The muscular and connective tissue components of the digestive tract are derived from splanchnic mesenchyme surrounding the primitive gut.
The FOREGUT gives rise to:
* the pharynx,
* the lower respiratory system,
* the esophagus,
* the duodenum (proximal to the opening of the bile duct),
* the liver,
* the pancreas,
* and the biliary apparatus.
Because, trachea and esophagus have a common origin, imcomplete partitioning of the trachoesophageal septum results in stenoses or atresias, with or without fistulas between them.
Development of the liver
The liver bud or hepatic diverticulum is formed from an outgrowth of the endodermal epithelial lining of the foregut , The epithelial liver cords and primordia of the biliary system which develop from the hepatic diverticulum, grow into the mesenchymal septum transversum . Between the layers of the ventral mesentery, derived from the septum transversum, these primordial cells differentiate into the parenchyma of the liver and the lining of the ducts of the biliary system.
* Hemopoiesis in the liver starts on week 6.
* Bile formation starts on week 12.
Development of the duodenum
Congenital duodenal atresia is due to the failure of vacuolization and recanalization (week 8; ). This process occurs following the normal solid stage of the duodenum (week 5). Obstruction of the duodenum can also be caused by an annular pancreas , resulting from parts of the pancreas developing around the duodenum.
Development of the pancreas
The pancreas is formed by dorsal and ventral pancreatic buds originating from the endodermal lining of the foregut. When the duodenum rotates to the right, the ventral pancreatic bud moves dorsally and fuses with the dorsal pancreatic bud. The ventral pancreatic bud forms most of the head of the pancreas and the dorsal pancreatic bud forms the rest. If the duct systems from each pancreas fail to fuse, an accessory pancreatic duct forms.
The MIDGUT gives rise to:
* the duodenum distal to the bile duct,
* the jejunum,
* the ileum,
* the cecum,
* the vermiform appendix,
* the ascending colon,
* and the right 1/2 to 2/3 of the transverse colon.
The midgut forms a U-shaped intestinal loop herniating into the umbilical cord during week 6 because of the lack of room in the abdomen : This is the physiological umbilical herniation
* While in the umbilical cord, the midgut loops rotates 90 degrees counterclockwise
* During week 10, the intestines return to the abdomen, rotating a further 180 degrees . This is the reduction of the midgut hernia.
Omphalocele malrotations and abnormalities of fixation result from failure of return or abnormal rotation of the intestines in the abdomen. Because the gut is normally occluded during weeks 5 and 6 due to rapid mitotic activity of its epithelium, stenosis, atresias and duplications ) may result if the recanalization fails to occur or occur abnormally.
Various remnants of the yolk stalk may persist such as Meckel’s (ileal) diverticulum ) which can become inflamed and produce pain.
The Hindgut gives rise to:
* the left 1/3 to 1/2 of the transverse colon,
* the descending colon,
* the sigmoid colon ,
* the rectum,
* and the superior part of the anal canal.
The inferior part of the anal canal develops from the proctodeum
The caudal part of the hindgut (the cloaca; ) is divided by the urorectal septum into the urogenital sinus and rectum. The urogenital sinus gives rise to the urinary bladder and urethra. The rectum and superior anal canal are separated from the outside by the anal membrane which breaks down by the end of week 8.
* Anorectal malformations result from abnormal partitioning of the cloaca by the urorectal septum into the rectum and anal canal posteriorly and the urinary bladder and urethra anteriorly (
* Arrested growth and/or deviation of the urorectal septum in a dorsal direction causes most of the anorectal abnormalities such as rectal atresia and fistulas between the rectum and urethra, urinary bladder or vagina.
Urogenital system embryology
The Developing Human – Clinically Oriented Embryology – Moore and Persaud, 8th edition – Chapter 12
The urogenital system develops from:
* the intermediate mesoderm (
* the mesodermal epithelium (mesothelium) of the peritoneal cavity,
* and the endoderm of the urogenital sinus (
The intermediate mesoderm used to lie lateral to the somites, then moved away from the somites during the lateral fold. It forms the urogenital ridge ( ) which is comprised of:
* a nephrogenic cord or ridge
* and a gonadal or genital ridge
3 successive sets of kidneys develop:
* The nonfunctional, rudimentary pronephroi develop early in week 4. But they degenerate, leaving behind the pronephric ducts which run to the cloaca . These ducts will remain for other kidneys.
* The mesonephroi develop later during week 4, serving as temporary excretory organs.
* The functional metanephroi or permanent kidneys develop early in week 5. They are functional by week 11-13 and excrete urine into the amniotic fluid. This excretion continues during fetal life and the fetus swallows this urine mixed in the amniotic fluid. It is then absorbed in the stomach and duodenum to the blood for transport to the placenta and disposal.
o If renal agenesis or urethral obstruction occurs, oligohydramnios results.
o If esophageal or duodenal atresia occurs, then polyhydramnios results.
The metanephros develops mesodermally from the metanephric diverticulum or ureteric bud which is a dorsal outgrowth from the mesonephric duct near the cloaca
* Its stalk gives rise to the ureter
* its cranial end to the renal pelvis,
* its first 4 generations of tubules to the major calyces,
* its second 4 generations to the minor calyces (
* and the remaining generations of tubules to the collecting tubules (
The metanephric diverticulum or ureteric bud penetrates the metanephric mesoderm in the caudal part of the nephrogenic cord and stimulates the formation of the metanephric mass or cap
The metanephric mesoderm gives rise to the nephrons (glomerulus, Bowman’s capsule, proximal convoluted tubule, loop of Henle and distal convoluted tubule; ). The cortex of the kidney in the newborn contains mostly undifferentiated mesenchyme; the nephrons continue to develop several months after birth.
Ascension of the kidneys ( ): The kidneys are first located in the pelvis ventral to the sacrum but gradually ascend to the abdomen. They reach the adult position by week 9 having touched the suprarenal glands ( ). This is due to the disproportionate growth between the lumbar and sacral regions: the sacral region grows faster than the lumbar region.
The kidneys rotate 90 degrees from anterior to medial.
During their ascension, the blood supply changes continuously so that an adult may have 2 to 4 renal arteries (
The suprarenal glands
* The cortex forms from the mesoderm,
* the medulla from neural crest cells (receiving preganglionic sympathetic fibers from the celiac plexus).
The urinary bladder develops from the urogenital sinus and the surrounding splanchnic mesenchyme ( ). The urogenital sinus is comprised of 3 regions:
* The cranial or vesical region which will form the bladder and which is attached to the allantois. After birth, the allantois degenerates and becomes the urachus forming the median umbilical ligament. The transitional epithelium of the bladder develops from endoderm of the urogenital sinus.
* The middle or pelvic region.
* and the caudal or phallic region.
The female urethra and almost all of the male urethra have the same origin.
The glans penis in the male develops from the ectodermal glandular plate (
Developmental abnormalities of the kidney and excretory passages are common:
* Incomplete division of the metanephric diverticulum or ureteric bud results in double ureter ( ) and supernumerary kidney
* Failure of the kidney to “ascend” from its embryonic position in the pelvis results in an ectopic kidney that is abnormally rotated (
* Various congenital cystic conditions of the kidneys may result from failure of nephrons derived from the metanephric mesoderm to connect with collecting tubules derived from the metanephric diverticulum.
THE GENITAL OR REPRODUCTIVE SYSTEM develops in close association with the urinary or excretory system.
Genetic sex is established at fertilization, but the gonads do not begin to attain sexual characteristics until week 7. Early genital development is referred to as the indifferent stage of sexual development: the external genitalia do not acquire distinct masculine or feminine characteristics until week 12.
Testes and ovaries are derived from the mesodermal epithelium (mesothelium) lining the posterior abdominal wall, the underlying mesenchyme and the primordial germ cells.
The primordial germ cells form in the wall of the yolk sac during week 4 ( They later migrate into the developing gonads at week 6 and differentiate into the definitive germ cells (oogonia/spermatogonia).
The reproductive organs in both sexes develop from primordia that are identical at first.
* Gonads develop at week 5 from thickened mesodermal epithelium on the medial side of the mesonephros, at the gonadal ridge (.).
* Primary epithelial sex cords grow into the underlying mesenchyme (.
* During this indifferent stage, an embryo has the potential to develop into either a male or a female. The indifferent gonads consist of a cortex and medulla.
* In the male (XY) the cortex regresses and the medulla develops ( The reverse occurs in the female (XX).
At first both the male and the female have 2 pairs of genital or sex ducts: the mesonephric (wolffian – medial) and paramesonephric (müllerian – lateral) ducts .
Gonadal sex is determined by the Y chromosome, which exerts a positive testis-determining action (TDF) on the indifferent gonad.
* In the presence of a Y chromosome, testes develop and produce an inducer substance stimulating development of the mesonephric ducts into the male genital ducts (epididymis, vas deferens and ejaculatory ducts; ). Androgens from the fetal testes stimulate development of the indifferent external genitalia into the penis and scrotum. A suppressor substance (müllerian inhibiting substance), also produced by the testes, inhibits development of the paramesonephric ducts.
* In the absence of a Y chromosome and in the presence of 2 X chromosomes, ovaries develop, the mesonephric ducts regress, the paramesonephric ducts develop (fig. 12-33B-C). The superior end of these ducts open into the future peritoneal cavity. The lower end becomes the uterus and uterine tubes
* The vagina develops from the vaginal plate derived from the urogenital sinus, and the indifferent external genitalia develop into the clitoris and labia .
Persons with true hermaphroditism (ovo-testes – very rare) have both ovarian and testicular tissue and variable internal and external genitalia.
Errors in sexual differentiation cause pseudohermaphroditism.
* Male pseudohermaphroditism results from failure of the fetal testes to produce adequate amounts of masculinizing hormones, or from production of the hormones after the tissue sensitivity of the sexual structures has passed. Subjects are chromosomally male.
* Female pseudohermaphroditism results from virilizing adrenal hyperplasia, a disorder of the fetal suprarenal or adrenal glands that causes excessive production of androgens and masculinization of the external genitalia. Subjects are chromosomally female.
* Androgen insensitivity syndrome:
o Previously called testicular feminization syndrome.
* Most abnormalities of the female genital tract result from incomplete fusion of the paramesonephric ducts ,
* Cryptorchidism (undescended testes; ) and ectopic testes result from abnormalities of testicular descent (The gubernaculum guides the processus vaginalis into the scrotum and the testes follow; ).
* Congenital inguinal hernia ( ) and hydrocele (peritoneal fluid in the processus vaginalis and spermatic cord; ) result from persistence of the processus vaginalis (communication between the tunica vaginalis and the peritoneal cavity).
* Failure of the urogenital folds to fuse normally in males results in various types of hypospadias (opening of the external urethral orifice on the ventral surface of the glans penis or on the ventral surface of the body of the penis; ) or epispadia.
EMBRYOLOGY OF THE BRANCHIAL ARCHES AND DERIVATIVES
The Developing Human – Clinically Oriented Embryology – Moore and Persaud, 8th edition – Chapter 9
The branchial apparatus consists of
Branchial or pharyngeal arches
* Pharyngeal pouches
* Branchial grooves
* Branchial membranes
Most congenital malformations of the head and neck originate during transformation of the branchial apparatus into its adult derivatives.
The primitive mouth or stomodeum is separated from the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane ( ). This membrane ruptures at about day 24 ( ), bringing the primitive gut into contact with the amniotic fluid cavity.
Branchial arches develop early in week 4 as neural crest cells migrate to the future head and neck region.
By the end of week 4, 4 pairs of branchial arches are visible, the 5th and 6th being small. Branchial arches are separated by the branchial grooves and are numbered in a craniocaudal sequence ,
Initially, each pharyngeal arch consists of mesenchyme derived from the intraembryonic mesoderm and is covered with ectoderm externally and endoderm internally.
Neural crest cells migrate into the arches, creating the swellings of the arches and contributing to the arches, even though they are of ectodermal origin. Neural crest cells give rise to specific skeletal structures.
The mesenchyme in the arches give rise to muscles.
A typical branchial arch contains
* an aortic arch
* a cartilaginous rod
* a nerve
* a muscular component
Derivatives of the branchial arch cartilages
1st branchial (mandibular) arch cartilage develops :
* into malleus and incus (middle ear bones) from its dorsal portion
* into the anterior ligament of the malleus and the sphenomandibular ligament from the perichondrium of its intermediate portion
* into the primordium of the mandible from its ventral portion
2nd branchial (hyoid) arch cartilage develops:
* into the stapes (middle ear) and the styloid process from its dorsal part
* into the stylohyoid ligament from the perichondrium of its intermediate part
* into the lesser cornu and the superior part of the hyoid bone from its ventral part
3rd branchial arch cartilage develops into the greater cornu and inferior part of the body of the hyoid bone.
4th and 6th branchial arch cartilages fuse to form the laryngeal cartilages, except for the epiglottis which forms from the mesenchyme in the hypobranchial eminence (from the 3rd and 4th branchial arches).
Derivative of the branchial arch nerves
* 1st branchial arch: Trigeminal (V) nerve (maxillary and mandibular divisions only)
* 2nd branchial arch: Facial (VII) nerve
* 3rd branchial arch: Glossopharyngeal (IX) nerve
* 4th and 6th branchial arches: Vagus (X) nerve
Derivatives of the branchial arch muscles
1st branchial arch:
* Muscles of mastication
* Mylohyoid and anterior belly of the digastric
* Tensor tympani
* Tensor veli palatini
2nd branchial arch
* Muscles of facial expression
* Posterior belly of the digastric
3rd branchial arch
4th and 6th branchial arches:
* Levator veli palatini
* Constrictors of the pharynx
* Intrinsic muscles of the larynx
* Striated muscles of the esophagus
PHARYNGEAL POUCHES ( ) develop between the branchial arches (1st pouch is found between the first and second branchial arches). There are 4 pairs, the 5th is absent or very small.
The endoderm of the pharyngeal pouches and the ectoderm of the branchial grooves contact each other to form the branchial membranes separating the pharyngeal pouches and the branchial grooves.
Derivatives of the pharyngeal pouches (
1st pharyngeal pouch expands into a tubotympanic recess (
* The expanded distal portion of the recess contacts the 1st branchial groove (this is the only branchial membrane to persist in the adult) contributing to the formation of the tympanic membrane or eardrum.
* Only the 1st branchial groove persists in the adult as the external acoustic meatus ( ).
* The tubotympanic recess gives rise to the tympanic cavity and the mastoid antrum. Connection between the tubotympanic recess and the pharynx elongates to form the auditory tube.
2nd pharyngeal pouch contributes to the formation of the palatine tonsil ( ) and the epithelial lining of the fauces.
3rd pharyngeal pouch contributes to the formation of the inferior parathyroid glands (week 5- bulbar portion ) and the thymus (elongate portion). which migrate inferiorly (past the superior parathyroid glands of the 4th pouch).
4th pharyngeal pouch contributes to the formation of the superior parathyroid gland (bulbar portion) and the parafollicular cells or calcitonin cells of the thyroid gland (elongate portion – ultimobranchial body).