EMBRYOLOGY

NOTE: All time classifications are post-Conception, not post-LMP

1. DEVELOPMENT OF FOLLOWING ORGANS:

· HEART (pg. 93 of Carlson)

A. Embryologic structure giving rise to organ: Week 3; Derived from mesoderm

1. Heart-forming mesoderm migrates through primitive streak to form bilateral fields of precardiac splanchnic mesoderm within Cardiogenic region, which lies in the cephalic region of the embryoà

· Outflow tract of heart: Most cranial part of primitive streak

· Inflow tract of heart: Most posterior part of streak

2. Precardiac splanchnic mesoderm develops into bilaterally paired endocardial heart tubesà

3. Lateral and cephalocaudal folding causes the heart tubes to join together and lie in a ventral location, between the primitive mouth and the foregut à forms the primitive heart tube

4. The primitive heart dilates into five areas, shown in the figure below

B. Development of the Primitive Heart Tube:

Endocardium: Lateral folding occurs à endocardial heart tubes fuse to form the primitive heart tube à Develops into Endocardium

Myocardium and Epicardium: Mesoderm surrounding the primitive heart tube à develops into Myocardium and Epicardium

Five Dilatations of Primitive Heart tube and adult derivations

1. Truncus arteriosus à proximal aorta and proximal pulmonary artery

2. Bulbus cordis à smooth parts of the right ventricle (conus arteriosus) and left ventricles

3. Primitive ventricle à right and left ventricles

4. Primitive atrium à right and left atria

5. Sinus Venosus à smooth part of right atrium, the coronary sinus, and oblique vein

• LUNG (pg. 341-342 Carlson)

A. Embryologic structure giving rise to organ: Week 4; forms from foregut: the lining of the lower respiratory tract is drived from endoderm, while the connective tissue cartilage and muscle are derived from mesoderm.

1. Week 4: Mesodermally derived ventral wall of the foregut forms laryngotracheal grooveà

2. Week 5: Out growth of the laryngotracheal groove gives rise to Respiratory diverticulum à grows into the splanchnic mesoderm parallel to the esophagus à

3. Through a series of interactions with surrounding mesoderm, the Respiratory diverticulum elongates into a tracheal portion and begins to form the first of 23 sets of bifurcations à giving rise to lung buds.

NOTE: Bifucations continue into postnatal life (age 8)

B. Facts about the respiratory diverticulum:

Derivatives: Distal end of Respiratory Diverticulum enlarges à forms Lung bud, which divides à forms two bronchial buds that branch à forms the primary, secondary, and tertiary bronchi

Relationship with Foregut: a. Initially in open communication with foregut

b. Communication is eventually obliterated by formation of tracheoesophageal septum, which separates the trachea from the esophagus.

C. Four Periods of Lung development: (see High Yield figure 10-3 and Table 10-1 on back)

1. Glandular: weeks 5-16

a. Embryonic stage (weeks 4-7):

· Initial formation of the respiratory diverticulumà formation of all major bronchopulmonary segments.

· Lungs growing to fill bilateral pleural cavities

· Lungs become major component of the thoracic body cavity above the pericardium

b. Pseudoglandular stage (weeks 8-16):

· Period of major formation and growth of the duct systems within the bronchopulmonary segments before their terminal portions form respiratory components

· The primary bronchi are formed, followed by secondary, tertiary and segmental bronchi.

· Histological structure of the lung resembles that of a gland, thus providing the basis of the name of this stage.

· Viability: Respiration is not yet possible in this stage.

2. Canalicular: weeks 17-26

· Characterized by the formation of respiratory bronchioles

· Intense ingrowth of blood vessels into the developing lungs à Close association of capillaries with the walls of the respiratory bronchioles

· Viability: Occasionally a fetus born toward the end of this period can survive with Intensive care, but respiratory immaturity is the principal reason for poor viability.

3. Terminal Sac: weeks 26-birth

· Alveoli (terminal air sacs) bud off the respiratory bronchioles

· Epithelium lining the alveoli differentiates into two types of cells:

a. Type I (blood-air barrier)à Pneumocytes: Gas exchange occurs across these cells after birth

b. Type II (surfactant-producing)à Secretory Epithelial Cells: Form pulmonary surfactant (reduces surface tension, facilitates expansion of the alveoli during breathing)

c. NOTE: Type II form first, after proliferation some lose secretory function and flatten to form Type I cells

· Viability: Respiration is possible after week 25.

4. Alveolar or Postnatal stage: Birth - 8 years of age

· Most of the alveoli develop after birth.

· At Birth: Only 10% of the alveoli of a mature lung formed

· Mechanism of increase in number of alveoli after birth:

a. Accounts for 90% of alveoli of mature lung

b. Formation of secondary connective tissue septa that divide existing alveolar sacs

· As the child grows, the lung increases in size due to proliferation of respiratory bronchioles and terminal sacs.

• LIVER

A. Embryologic structure giving rise to organ: Week 3; dervived from Endoderm

Endodermal cells from the floor of the foregut à give rise to hepatic diverticulum

B. Hepatic diverticulum à Liver formation:

1. Endodermally derived Hepatic diverticulum sends hepatic cell cords into surrounding mesoderm called the septum transversum à

2. Hepatic cords form a series of loosely packed and highly irregular sheets that alternate with mesodermally lined sinusoids, through which blood percolates and exchanges nutrients with the hepatocytesà

3. The entire liver soon becomes too large to be contained in the septum transversum, and it protrudes in the ventral mesentery within the abdominal cavity Liver bulges into abdominal cavity and septum transversum is stretched to form the ventral mesentery

4. NOTE: Septum tranversum also plays a role in the formation of the diaphragm, thus the close adult anatomic relationship between the liver and diaphragm.

• KIDNEY (pg. 40 – 41 High Yield Embryo; pg 359-365 in Carlson)

A. Embryologic structure giving rise to organ: Day 22; derived from intermediate mesoderm

1. Cells from the anterior intermediate mesoderm à differentiate to form the Nephrogenic cord (epithelial cords) à

2. Nephrogenic cord grows caudally toward the cloaca to form à the Pronephros, mesonephros, and metanephros (adult kidney)

3. Lim-1 and Pax 2 are important in this early stage of kidney development

B. Prosnephros:

1. Timeline: Forms in the week 4; regresses during week 5

2. Function: Not functional and completely regresses

3. Development: Nephrogenic cord connects laterally with a pair of primary nephric (pronephric) ducts growing toward the cloaca

C. Mesonephros:

1. Timeline: Forms in week 4; is functional until the permanent kidney is able to develop in week 9

2. Function: Filters and removes body wastes for a short period and regresses completely except for Mesonephric (wolffian) duct and some of the mesonephric tubules:

· In male only: Forms the ductus deferens, epididymis, ejaculatory duct, and seminal vesicle

· In male and female: Forms the ureteric bud from which are derived the ureter, renal pelvis, calyces, and collecting tubules.

· In female only: No important genital or reproductive derivatives of the mesonephric duct specific to females are formed.

3. Development:

a. Nephrogenic cords extend caudally à Stimulates intermediate mesoderm to form additional segmental sets of tubules à

b. Each mesonephric tubule empties separately into the continuation of the Nephrogenic cord, which becomes known as the mesonephric (wolffian) duct.

4. WT-1 regulates the transformation from mesenchyme to epithelium during formation of mesonephric tubules

D. Metanephros (Adult kidney):

1. Timeline: Forms during week 5 from interaction between ureteric bud and metanephrogenic blastema; begins to function week 9.

2. Function: Filters and removes body wastes for life; Concentrates urine

3. Development:

a. Begins early in Week 5 when ureteric bud (metanephric diverticulum) grows into the posterior portion of the intermediate mesoderm à

b. Mesenchymal cells of intermediate mesoderm condense around the ureteric bud to form à metanephrogenic blastema (fig. 15-1 pg 360 of Carlson)

c. Undifferentiated mesenchyme of the metanephrogenic blastema secretes GDNF (glial cell line-derived neurotrophic factor) à GDNF causes the outgrowth of the ureteric bud from the mesonephric duct à

d. In response to GDNF, the ureteric bud produces FGF-2, BMP-7 and Wnt-11, which induce the metanephric mesenchyme to form à the epithelial precursors of renal tubules

e. Adult derivatives:

i. Ureteric bud: differentiates to form the collecting duct, minor calyx, major calyx, renal pelvis and ureter

ii. Metanephrogenic blastema: differentiates to form the primitive renal tubules, which differentiate to form à the renal glomerulus, bowman’s capsule, proximal convoluted tubule, loop of Henle, distal convoluted tubule and the connecting tubule

iii. Nephronsà formation involves three metanephric mesodermal cell lineages: 1) Epithelial cells derived from the ureteric bud, 2) Mesenchymal cells from the metanephrogenic blastema and 3) Ingrowing vascular endothelial cells

3. WT-1 regulates the formation of GDNF in the metanephric mesenchyme; c-Ret (a member of the tyrosine kinase receptor superfamily) binds GDNF.

5. Ascent of the kidneys:

a. Fetal metanephros (located in the sacral region) ascends to level T12-L3, due to the disproportionate growth of the embryo caudal to the metanephros

b. During the ascent, kidneys rotate 90 degrees medially, causing the hilum to orientate medially

c. Blood supply: Changes during ascent until the definitive renal arteries develop at L2; Arteries formed during the ascent may persist and are called supernumerary arteries.

2. IMPORTANT CONGENITAL MALFORMATIONS:

• NEURAL TUBE DEFECTS: (pg 241-243, Carlson; pg 1299-1300, Robbins)

1. Definition: Failure of portion of neural tube to close or a re-opening of a region of the tube after closure; malformations are characterized by abnormalities involving both neural tissue and overlying bone or soft tissue

2. Timeline: Closure of the neural tube first occurs in the region where the earliest somites appear à closure spreads both cranially and caudally

a. Closure of the cranial neuropore: 24 days gestation

b. Closure of the caudal neuropore: 26 days gestation

3. Etiology: Unknown; frequency varies widely among ethnic groups; Folate deficiency during initial weeks of gestation is implicated as a risk factor

4. Clinical Presentation: Dysfunction related to structural abnormality caused by condition and to superimposed infection that extends from the thin overlying skin

5. Diagnosis: Screen blood for elevated levels of alpha-fetoprotein or by US scanning

• CONGENITAL MALFORMATIONS OF THE NERVOUS SYSTEM

CONDITION	CLINICAL FEATURES
Fetal Alcohol Syndrome	· Most common cause of mental retardation · Cardiac septal defects · Facial malformations including widely spaced eyes and long philtrum · Growth retardation
Spina bifida	· Improper closure of posterior neuropore · Several forms: 1. Spina bifida occulta (mildest form) – failure of vertebrae to close around spinal cord (tufts of hair often evident) 2. Spinal meningocele (spina bifida cystica) – meninges extend out of defective spinal canal 3. Meningomyelocele – meninges and spinal cord extend out of spinal canal 4. Rachishisis (most severe form) – neural tissue is visible externally
Hydrocephaly	· Accumulation of CSF in ventricles and subarachnoid space · Sue to congenital blockage of cerebral aqueducts · May be caused by Cytomegalovirus or toxoplasma infection
Anencephaly	· Failure of brain to develop · Due to lack of closure of anterior neuropore · Associated with increased alpha-fetoprotein (AFP)
Arnold-Chiari syndrome	· Herniation of the cerebellar vermis through the foramen magnum · Hydrocephaly · Myelomeningocele

• CLEFT PALATE: (pg. 303-305, Carlson; pg 67-68, High yield)

1. Definition: An incomplete or absent fusion of the palatal shelves (Figures 13-17 and 13-18, pg 304 of Carlson). Extent of palatal clefting ranges from involvement of the entire length of the palate to bifid uvula.

· Incidence: 1 in 2500 births

· Three types à Anatomic landmark that separates anterior from posterior is the Incisive foramen

a. Anterior cleft palate: Occurs when the palatine shelves fail to fuse with the primary palate

b. Posterior cleft palate: Occurs when the palatine shelves fail to fuse with eachother and with the nasal septum

c. Anteroposterior cleft palate: Occurs when there is a combination of both defects

2. Timeline: Palate forms between weeks 6-10; closure occurs 1 week later in females than males

3. Etiology: As with cleft lip, cleft palate is usually multifactorial. High incidence à

a. Congenital: Trisomy 13 and other chromosomal syndromes

b. Chemical teratogen: Anticonvulsant medications and exposure to Cortisone (genetic component to this as well)

4. Clinical Presentation: Higher incidence in females may be related to the palatal shelves fusing about a week later than they do in males, thus prolonging the susceptible period.

· CLEFT LIP: (pg. 303-305, Carlson; pg. 68 High yield)

1. Definition: Lack of fusion of the maxillary and nasomedial prominences (Figures 13-17, pg 303 of Carlson).

· Incidence: 1 in 1000 births

· Two types à

a. Unilateral: Most common congenital malformation of the head and neck.

b. Bilateral: The most complete form, the entire premaxillary segment is separated from both maxillae à Bilateral clefts run through the lip and upper jaw between the lateral incisors and the canine teeth è The point of convergence of the two clefts is the Incisive foramen (Figure 13-8, Carlson pg. 295)

2. Timeline: Lip forms with structures of the face between weeks 4-8

3. Etiology: As with cleft palate, cleft lip is usually multifactorial.

a. Common mechanisms:

1) Hypoplasia of the maxillary process, preventing contact between the maxillary and nasomedial processes from being established.

2) The underlying somitomeric mesoderm and neural crest fail to expand, resulting in a persistent labial groove

b. Chemical teratogen: Retinoic acid à excess inhibits the outgrowth of the frontonasal and nasomedial processes.

4. Clinical Presentation: Difficulty eating and drinking

• TETROLOGY OF FALLOT (pg. 437, Figure 16-33 Carlson; pg28, Figure 6-2 High Yield)

1. Definition: Characterized by à 1) Pulmonary Stenosis 2) Membranous Interventricular Septal Defect 3) An Overriding Aorta (opening extends into the right ventricle) and 4) Right Ventricular Hypertrophy

· Incidence: Most common cyanotic heart lesion

2. Timeline:

3. Etiology: Basic defect is an asymmetrical fusion of the truncoconal ridges and the malalignment of the aortic and pulmonary valves à Result of abnormal neural crest cell migration such that there is skewed development of the Aorticopulmonary septum

4. Clinical Presentation: Cyanosis results from poorly oxygenated right ventricular blood exiting via the enlarged aorta to systemic circulation (may not be present at birth); R àL shunt; boot-shaped heart

OVERVIEW OF CONGENITAL DEFECTS OF THE HEART AND GREAT VESSELS

ANOMALY	PATHOLOGY	CLINICAL PRESTATION	NOTES
Atrial Septal defect (ASD)	Endocardial cushion defect à Defect of septum primum or septum secundum à Secundum ASD account for 90%	· Left-to-right shunt · Asymptomatic into 4^th decade · Murmur · Right Ventricular hypertrophyq	Much higher incidence in females (3:1) Down syndrome is associated with endocardial cussion defects
Coarctation of the aorta	Infantile: Proximal to PDA Adult: Constriction at closed ductus arteriosus, distal to origin of left subclavian artery	· Symptoms depend on extent of narrowing · Infant: Presents with lower limb cyanosis and right heart failure at birth · Adult: Asymptomatic with upper limb hypertension, rib notching on radiograph (from collateral circulation through intercostals arteries), and weak pulses in lower limbs	Much higher incidence in males (3:1) and females with Turner’s syndrome
Patent Ductus arteriosus (PDA)	àFailure of closure of the ductus arteriosus àMay be due to premature birth with hypoxemia or structural defects	· Continuous machinery murmur · RX: DA normally closes in the first days of life. Exposure to oxygenated blood alters the production of prostaglandins (PGs). Indomethacin, a PG synthesis inhibitor, induces closure of a PDA, while Alpostadil (PGE1) therapy maintains patency	Second most common CHD
Tetrology of Fallot	àDefective development of the infundibular septum; àResults in overriding aorta, ventricular septal defect, pulmonary stenosis, hypertrophy of the right venticle	· Cyanosis (may not be present at birth) · Right-to-left shunt · Boot-shaped heart	Survival to adulthood possible; patient assumes squatting position to relieve symptoms
Transposition of the great vessels	àAorta drains right ventricle; àPulmonary artery drains left ventricle Separate pulmonary and systemic circuits	· Incompatible with life unless shunt present · Cyanosis (present at birth)	Diabetic mother is risk factor
Ventricular septal defect (VSD)	Endocardial cushion defect àMembranous VSD (90%) àSingle muscular VSD (10%)	· Left-to-right shunt · Small defect: Loud holosystolic murmur; can close spontaneously · Large defect: Can present as heart failure at birth	Much higher incidence in males; most common congenital heart defect (33%); Down syndrome is associated with endocardial cussion defects
Eisenmenger’s syndrome èchange from left-to right shunt to a right-to-left shunt secondary to increasing pulmonary hypertension · Usually occurs due to chronic, adaptive response to pre-existing left to right shunts, such as a VSD

TRACHEOESOPHAGEAL FISTULA (pg. 346, Figure 14-26 Carlson; pg 55-56, Figure 10-2 High Yield)

1. Definition: Abnormal communication (fistula) between the trachea and the esophagus, which is caused by improper formation of the tracheoesophageal septum. The most common type (90 % of all cases) is esophageal atresia (ends in blind pouch) with a fistula between the esophagus and the distal one-third of the trachea

· Incidence: Most common family of malformations of respiratory tract

2. Etiology: Related to abnormal separation of the tracheal bud from the esophagus at level of larynx during early development of the respiratory system. Associated with esophageal atresia and polyhydramnios

3. Clinical Presentation:

· Excessive accumulation of saliva or mucus in the infant’s nose and mouth

· Episodes of gagging and cyanosis after swallowing milk

· Abdominal distention after crying

· Reflux of gastric contents into the lungs à Pneumonitis

HORSHOE KIDNEY: (pg. 372, Carlson; pg. 43-44 High yield)

1. Definition: Kidneys are fused at their inferior poles, and they cannot migrate out of the pelvic cavity because the inferior mesenteric artery, coming off the aorta, blocks them from ascending.

· Incidence: 1 in 400 births

2. Timeline: Fusion occurs during development of metanephros, between week 5 and week 9

3. Clinical Presentation:

· Most are asymptomatic, but occasionally pain or obstruction may occur

· Pelvic Kidneys are subject to an increased incidence of infections and obstructions of the ureters

OVERVIEW OF CONGENITAL RENAL ANOMALIES

ANOMALY	CHARACTERISTICS
Bilateral renal agenesis Aka Potter’s syndrome	· Etiology: Occurs when the ureteric bud does not form · Clinical Presentation: Oligohydramios · Limb deformities · Facial deformities · Pulmonary hypoplasia · Viability: Bilateral agenesis is not compatible with life
Accessory Renal arteries	· Features: Arise from aorta · Feet section of the kidney · Are end arteries · Cutting will produce ischemic infarct of area they supply
Congenital polycystic kidney disease	· Features: Multiple small and large cysts causing renal insufficiency · Cysts are “closed” --- not continuous with collecting system · Evident at birth · Viability: Death within days to weeks
Horseshoe kidney	· Features: Inferior poles of kidneys are fused · Ascent is arrested at the level of the inferior mesenteric artery · Increases probability of Wilm’s tumor

3. DEVELOPMENT OF THE CENTRAL NERVOUS SYSTEM

• CNS includes the brain and spinal cord; Formed from neural tube

1. The basal plate of the neural tube à motor neurons.

2. The alar plate of the neural tube à sensory neurons.

3. The basal and alar plates are separated by the sulcus limitans.

• Oligodendrocyte formation: (Myelination) Formed from month 4 of conception to year two of life
• Conus medullaris: Distal end of spinal cord; At level of third lumbar vertebra (L3) at birth. As the body grows, the cord “ascends” to its final resting position at the first lumbar vertebra (L1)
• During Week 4, rostral part of neural tube forms three primary vesicles:
1. Prosencephalon – Forebrain;
2. Mesencephalon – Midbrain;
• FGF-8, Wnt-1, En-1, and Otx-2 play role in patterning
3. Rhombencephalon – Hindbrain;

· Hox complex and Krox-20 play role in patterning

· During Week 6, five secondary vesicles become apparent:

PRIMARY VESICLES	SECONDARY VESICLES	ADULT DERIVATIVES
Prosencephalon	Telencephalon Diencephalon	Cerebral hemispheres, caudate, putamen, amygdaloid, claustrum, lamina terminalis, olfactory bulbs, hippocampus Epithalamus, subthalamus, thalamus, hypothalamus, mamillary bodies, neurohypohysis, pineal gland, globus pallidus, retina, iris, ciliary body, optic nerve (CNII), optic ciasm, optic tract
Mesencephalon	Mesencephalon	Midbrain
Rhombencephalon	Metencephalon Mylencephalon	Pons, cerebellum Medulla

4. DERIVATIVES FO THE FOREGUT, MIDGUT, AND HINDGUT AS WELL AS THEIR VASCULAR SUPPLY

· Primitive gut tube:

1. Formation: Formed by the incorporation of a portion of the yolk sac into the embryo during craniocaudal and lateral folding.

2. Histology:

· Endodermal origin: Epithelial lining and glands of the mucosa

· Mesodermal origin: lamina propria, muscularis mucoae, submucosa, muscularisexterna, and adventitia/serosa

· Foregut Derivatives: Supplied by the Celiac artery

1. Esophagus à Tracheoesophageal septum divides the foregut into the esophagus and trachea

2. Stomachà Primitive stomach develops from a fusiform dilatation in the foregut during week 4. The stomach rotates 90 degrees clockwise during its formation

3. Liverà see above

4. Gallbladder and bile ductsà The connection between the hepatic diverticulum and foregut narrow to form the bile duct. Later, and outgrowth from the bile duct gives rise to the gallbladder and cystic duct.

5. Pancreasà The ventral pancreatic bud forms the uncinate process and part of the head of the pancreas; the dorsal pancreatic bud forms the remaining part of the head, body and tail of the pancreas; Acinar cells, duct epithelium, and islet cells are derived from endoderm

6. Upper duodenumà Develops from the caudal portion of the foregut.

7. NOTE: The junction of the foregut and midgut is just distal to the opening of the common bile duct.

· Midgut Derivatives: Supplied by the Superior mesenteric artery.

1. Jejunum 2. Ileum 3. Cecum 4. Appendix 5. Ascending colon 6. Proximal two thirds of the transverse colon

Formation: Week 6 à the midgut loop herniates through the primitive umbilical ring and causes a physiologic umbilical herniation. Week 11 à the midgut loop rotates 270 degrees counterclockwise around the superior mesenteric artery as it returns to the abdominal cavity, thereby reducing the physiologic umbilical herniation.

• Hindgut Derivatives: Supplied by the Inferior mesenteric artery.

1. Distal third of the transverse colon, descending colon, and sigmoid colon à From cranial end of the hindgut

2. Rectum and upper anal canal à terminal end of the hingut is a pouch called the cloaca; the cloaca is partitioned by the urorectal septum into the rectum, upper anal canal, and urogenital sinus

5. DERIVATIVES OF THE SOMITES; MALFORMATIONS ASSOCIATED WITH SOMITE MIGRATION

· Formation of the somites: (pg. 88-91, Carlson; pg. 106-107 High Yield)

1. Primitive node and streak regress toward caudal end of embryo à leave behind notochord and induced neural plate.

2. Lateral to neural plate, the paraxial mesoderm forms series of regular pairs of segments called somitomeres.

3. After ~20 pairs of somitomeres have formed caudally along the primitive node as it regresses, the first pair of somites forms behind the seventh pair of somitomeres The remaining caudal somitomeres further condense in a craniocaudal sequence to form 42-44 pairs of somites of the trunk region à the somites closest to the caudal end disappear to give a final count of approximately 35 pairs of somites. (Somitomeres 1-7 do not form somites but form pharyngeal arches, which contribute to the head and neck region).

4. Induction of the somites:

a. Segmentation of paraxial mesoderm à intrinsically controlled

b. Epithelialization of early somites à inductive signal from overlying ectoderm

c. Increased intercellular adhesive properties of presomatic cells – Transforms somite from mesenchyme to epithelium à induced by paraxis (helis-loop-helix)

· Ventral half of the somite à Sclerotome à Vertebral Body

1. Sonic hedghog (shh), originating from the notochord and ventral wall of neural tube, stimulates Pax-1 and Pax-9 response à Conversion back to mesenchymal morphology = Secondary mesenchyme

2. Secondary mesenchyme produces chondroitin sulfate proteoglycans and other cartilage matrix as they aggregate around the notochord à Forms vertebral body

· Dorsal half of somite à Dermomyotome à Myotome è Muscle

à Dermatome è Dermis

1. Wnt genes from the dorsal neural tube counteract the influence of sonic hedghog à Simulation of Pax-3, Pax-7, and paraxis à Maintains epithelial morphology à Forms Myotome and Dermatome

b. Myotome: Arises from mesenchymal cells from dorsomedial border of dermomyotome

i. Medial myoderm à Trunk musculature: Derived from myotomes in the trunk region

1. Dorsal epimere à Develops into the intrinsic back muscles (e.g., erector spinae); Innervated by the dorsal ramus of a spinal nerve

2. Ventral hypomere à Develops into the prevertebral, intercostals, and abdominal muscles; Innervated by the ventral ramus of a spinal nerve

ii. Lateral myoderm à Limb buds (under influence of BMP-4) à Limb musculature: Derived from myotomes in the upper and lower limb bud regions; this mesoderm migrates into the limb bud and forms a posterior condensation and an anterior condensation.

1. Posterior condensation à Develops into the extensor and supinator musculature of the upper limb and the extensor and abductor musculature of the lower limb.

2. Anterior condensation à Develops into the flexor and pronator musculature of the upper limb and the flexor and adductor musculature of the lower limb.

c. Dermatome: Arises from most dorsally located somatic epithelium à Dermis

			DORSAL
MEDIAL	DERMATOME à Dermis MYOTOME à Intrinsic back musles (epaxial)			DERMATOME à Dermis MYOTOME à Limb muscles à Muscles of ventrolateral body wall (hypaxial)	LATERAL
	SCLEROTOME à Vertebral body à Intervertebral disk à Proximal part of rib à Connective tissue			SCLEROTOME à Vertebral arch à Pedicle of vertebra à Distal part of rib à Connective tissue around dorsal root ganglion
		VENTRAL

· Malformations associated with somite migration:

ANOMALY	DESCRIPTION
Prune belly syndrome	· Abdominal musculature is absent or very hypoplastic, most likely involving cells of the hypomere
Poland’s Syndrome	· Relatively uncommon · Chest anomaly characterized by the partial or complete absence of the pectoralis major muscle · May demonstrate partial agenesis of the ribs and sternum, mammary gland aplasia, or absence of the latissimus dorsi and serratus anterior muscles
Congenital torticullis (wryneck)	· Sternocleidomastoid muscle is abnormally shortened causing rotation and tilting of the head · May be caused by injury to the sternocleidomastoid muscle during childbirth, formation of a hematoma, and eventual fibrosis of the muscle
Duchenne muscular dystrophy (DMD)	· Characteristic dysfunction: Progressive muscle weakness and wasting · Death occurs as a result of cardiac or respiratory failure, usually in the late teens or 20s · DMD is caused by a genetic mutation: 1. The DMD gene, located on the short (p) arm of chromosome X in band 21 (Xp21), encodes for a protein called dystrophin. This protein anchors the cytoskeleton (actin) of skeletal muscle cells to the extracellular matrix through a transmembrane protein ( alpha-dystroglycan and beta-dystroglycan) and stabilizes the cell membrane. 2. A mutation of the DMD gene destroys the ability of dystrophin to anchor actin to the extracellular matrix · DMD demonstrates an X-linked recessive inheritance

6. CHANGES IN THE CIRCULATORY/RESPIRATORY SYSTEM ON THE FIRST BREATH OF A NEWBORN (pg. 464 Carlson)

· Child birth results in almost instantaneous change in function due to altered circulatory balance and resulting structural changes in the circulatory system.

A. Circulatory changes at birth: Two major events drive the functional adaptations immediately following birth à Cutting of the umbilical cord and changes in the lungs after the first breaths.

1. Cutting the umbilical cord à Immediate cessation of blood entering the body via the umbilical vein (loss of 25%-50% of peripheral vasculature from placental circulation) à

· Eliminates major blood flow through the ductus venosus

· Decreases the amount of blood entering the right atrium via the inferior vena cava

Consequence è Decrease in stream of blood that was directly shunted from the R to L atrium duing fetal life

2. After a few breaths à Pulmonary circulation bed expands and can accomadate much greater blood flow

Consequence è Decreased blood flow through the ductus arteriosus and a correspondingly increased return of blood into the left atrium via pulmonary veins

· Within minutes after birth: Ductus Arteriosus undergoes reflex closure

à Result of increased Oxygen concentration in blood. (During fetal period, lower Oxygen concentration and high Prostaglandin E₂ kept it open)

à Shunt experiences a breakdown of elastic fibers and thickening of the inner intimal layer

· Subsequently: The blood pressure in the left atrium becomes slightly greater than that in the right atrium:

à Physiological closure of the interatrial shunt (foramen ovale) due to the pressure gradient

à Structural closure of the valve at the foramen ovale is prolonged and only completes several months after birth

Clinical correlation:

1. Probe patency à Before complete structural obliteration, the foramen ovale possesses the property of “probe patency”, which allow a catheter to be inserted into the right atrium to pass freely through to the left atrium

2. Probe patent Foramen ovale à In ~ 20% of individuals, the structural closure of the foramen ovale is not completed; asymptomatic condition.

· Later: Ductus Venosus loses physiologic patency immediately after birth, but its structural closure is more prolonged (Tissue wall is not as responsive to increased oxygen saturation as in ductuas arteriosus)

Postnatal Derivatives of Prenatal Circulatory Shunts or Vessels

PRENATAL STRUCTURE	POSTNATAL DERIVATIVE
· Ductus Arteriosus	· Ligamentum Arteriosum
· Ductus Venosus	· Ligamentum Venosum
· Interarterial shunt (Foramen ovale)	· Interarterial Septum
· Umbilical vein	· Ligamentum Teres
· Umbilical arteries	· Distal segments: Lateral Umbilical ligaments · Proximal segments: Superior vesical arteries

B. Lung Breathing in the Perinatal Period: Initial breaths are difficult because of fluid filled lungs and collapsed alveoli at birth. There are several mechanisms that ease this transition to regular and effective breathing necessary for survival

1. Trachea and Major airways: On a purely mechanical basis, air breathing is facilitated by a proportionally large diameter of the trachea and major airways à Reduces resistance to airflow

2. Arginine Vasopressin and Adrenalin: Just before birth, levels of these hormones increase à Suppress the secretion of fetal lung fluid and stimulate its resorption

· At birth the lungs contain ~ 50 ml alveolar fluid, which must be removed for adequate air breathing.

à ~50% enters lymphatic system

à ~25% expelled during birth

à ~25% enters the bloodstream

· Initial Breaths:

à Alveolar sacs begin to inflate on the first inspiration

à Pulmonary Surfactant reduces the surface tension at the air-fluid interface

à Pulmonary vasculature opens due to decreased resistance with rush of air into lungs à Results in increased oxygen saturation of the blood

è Clinical: The color of the newborn changes from dusky purple to pink

· Following weeks after birth:

à Breathing movements in the fetus are intermittent and irregular after birth

à Factors responsible for the transition from intermittent to regular breathing not well understood

à During periods of wakefulness: Breathing soon stabilizes

à For several weeks after birth: Short periods of apnea (5-10 seconds) are common during REM sleep

7. DEVELOPMENT OF THE EMBRYONIC PLATE IN WEEKS TWO AND THREE

NOTE: I spoke with Dr. Gest about this because I couldn’t find anything on the “embryonic plate.” He says they are probably referring to the “bilaminar germ disc,” so that is what I wrote about (High Yield pg 11-14; Carlson pg. 59-61)

· RECALL: The Blastocyst consists of the 1) Inner cell mass à arises from with the body of the embryo proper 2) Outer trophoblast à which represents the future tissue interface b/w embryo and mother

o The subdivision of the inner cell mass ultimately results in an embryonic body that contains the three primary embryonic germ layers: the ectoderm (outer layer), mesoderm (middle layer), and endoderm (inner layer).

1. Second Week (Day 8-14)

(See Figure 3-1 High Yield)

· Just before the embryo implants into the endometrum early in the second week (~ Day 8), cells of the inner cell mass rearrange into an epithelial configuration à A thin layer of cells appears ventral to the main cellular mass à The main upper layer of cells becomes the Epiblast, and the lower layer is the Hypoblast (aka. Primitive endoderm), forming a Bilaminar embryonic disk.

o Epiblast: Dorsal surface of Bilaminar disk

à Clefts develop within epiblast to form the amniotic cavity

à Extraembryonic somatic mesoderm lines the cytotrophoblast à forms Connecting stalk

o Hypoblast: Ventral surface of Bilaminar disk; Considered extraembryonic endoderm

à Hypoblast cells migrate along the inner surface of cytotrophoblast (~ Day 9) à lines with a continuous layer of extraembryonic endoderm è gives rise to the endodermal lining of the yolk sac (~ Day 10)

o Prochordal Plate: formed by the fusion of epiblast and hypoblast cells; Marks the future site of the mouth

2. Third Week (Day 15-21)

(See Figure 4-1 High Yield)

· Gastrulation: A process by which the three primary germ layers of ectoderm, mesoderm, and endoderm are formed from the EPIBLAST (no hypoblast involvement) migrating through the Primitive streak à Trilaminar embryonic disk. After gastrulation, the epiblast is called Ectoderm.

o Process is first indicated by the formation of the Primitive Streak within the dorsal surface of the epiblast:

à The Anteroposterior (craniocaudal) and right-left axes of the embryo can be readily identified after the formation of the Primitive streak

à The early primitive streak is a condensation caused by the converging of epiblastic cells at the extreme caudal end of the embryo à Expands cranially to form the Primitive groove leading to end of primitive streak where the Henson’s node (Primitive node) forms à Epiblast cells migrate to the primitive streak and insert themselves between the epiblast and hypoblast

· Some epiblast cells displace the hypoblast to form endoderm

· The remainder migrate cranially, laterally and along the midline to form mesoderm

o Ectoderm: Epiblast cells are channeled into a rodlike mass of mesenchymal cells called the Notocord, which induces the formation of the Neural tube. Gives further rise to è

à Neuroectoderm

à Neural crest cells

o Mesoderm: Gives rise to è

à Paraxial Mesoderm – Somitomeres and 35 pairs of somites

à Intermediate Mesoderm

à Lateral Mesoderm

o Endoderm: Epiblast cells displace the hypoblast (extraembryonic endoderm) after migrating through the primitive streak to form this intraembryonic endoderm

· All adult cells and tissues can trace their embryologic origin back to the three primary germ layers (see table 4-1 High Yield)