Anatomy Exam 2 Outline

Lecture 6: Blastogenesis
1. Development
a. Prenatal: fertilization to birth
i. Embryonic period: 1st – 8th week
ii. Fetal period: 9th week to birth
b. Postnatal: birth to adulthood
i. Infancy: first year of life
ii. Childhood: 1-11 years
iii. Adolescence: 11 to 19
iv. Adulthood: usually >20 years of age
2. Developmental processes
a. Cell division: growth
b. Cell migration: cells move to their final destination
c. Cell differentiation:
i. Generalized cell  more specific cell
ii. Undifferentiated  differentiated
iii. Totipotent  pluripotent  multipotent  fully differentiated
d. Cell to cell interaction: interaction with neighboring cells
e. Apoptosis: programmed cell death
3. Regulation of Development
a. Signaling molecules: Example Notch
i. Spans the plasma membrane – differentiate and activate adjacent cells
b. Cell adhesion molecules (CAMS)- Example Integrins and Cadherins
i. Connects internal cytoskeleton to other cells – interaction and attachment
ii. Guides migration
c. Secreted growth factors
i. Act directly and through concentration gradients
ii. Control cell growth and differentiation
iii. Major families of growth factors
1. Fibroblast Growth Factor (FGF): blood vessels, limb, brain, and axon growth
2. Hedgehog: nervous system, gut and limb, regional patterning
3. WNT: limb, brain, and urogenital differentiation
4. Transforming Growth Factor B (TGFB): cell division and migration, cell death
4. Timing of Development
a. Normally a tightly regulated time sequence
b. Events occurring too soon, too later or out of sequence will result in a malformation
i. Too early: palate shelves are not large enough to contact each other after they rotate
ii. Too late: upper jaw is now wider, normal sized palate shelves can not contact each other to fuse
5. Abnormal development
a. Disruption in developmental processes = malformation
i. Cell division
1. Too little or too much
a. Ex: Pre-auricular tag from excessive cell division
ii. Cell migration
1. Both number of cells and distance traveled
a. Ex: cleft lip from insufficient cell migration into the developing upper lip tissue
iii. Cell differentiation
1. Affects mature form and function
iv. Cell to cell interaction
1. Both migration and differentiation affected
v. Apoptosis
1. Creates openings or separates joined structures
2. Too little or too much
a. Ex: Webbed fingers from incomplete apoptosis

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 vi. Teratogen – agent that disrupts development
1. Pharmaceuticals, environmental pollutants, alcohol, cigarette smoke, infectious agents, excess
temperatures, radiation
vii. Environmental- gene interaction
viii. Critical periods: times of increased sensitivity
1. Exposure in critical period  major malformation
2. Exposure outside critical period  minor malformation or no effect

6. Developmental Origin of Adult Disease

a. Maternal exposure, emotions, health, nutrition and paternal nutrition and exposures  fetal development
i. Establishes known risk for
1. Hypertension, obesity, heart disease, asthma, Type II diabetes
ii. Establishes suspected risk for
1. Depression, schizophrenia, COPD, certain cancers, alcoholism, kidney disease
7. Days and Weeks of Pregnancy

8. The Fertilized Egg

a. Fertilized egg
i. Cytoplasm
ii. Pro nuclei
iii. Cell membrane
iv. Zona pellucida – glycoprotein layer, acts like a shell
b. Zygote
i. After fusion of the pro nuclei
ii. Cell division initiated
iii. Cleavage: cell division in zygote
1. Cell division is not coordinated; cells do not divide at the same time. This can result in zygotes with 5
or other odd numbers of cells
iv. Blastomeres: early embryonic cells, still enclosed in zona pellucida
1. Totipotent to the 8 cell stage
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 v. Identical twins result if cells separate
vi. After the 8 cell stage cells are pluripotent
c. The morula
i. Morula: 16+ cells, tightly compacted
ii. Inner cell mass will become the embryo proper
iii. Outer cell mass will become the trophoblast (the precursor of the placenta)
d. The blastocyst
i. Zona pellucida starts to disintegrate (day 5-6)
ii. Fluid enters, forming the blastocoel
iii. Embryo now called a blastocyst
iv. Early blastocysts still in the zona pellucida
v. Late blastocyst “hatches” from the zona pellucida, and expands rapidly
vi. Outer cell mass – now a single cell layer around the outside of the blastocoel
1. Called the trophoblast
2. Will form the placenta
vii. Inner mass pushed to one side
1. Now called the embryoblast
2. Located on the embryonic pole
3. Will become the embryo proper
e. Timing of Early Events
i. Fertilization occurs in the uterine tube near the ovary
ii. Each division takes ~ 20 hours
iii. Day 3-4: the 16 cell morula is formed
iv. Day 4-5: the 32 cell compacted morula enters the uterus
v. Day 5-6: the early blastocysts is formed
vi. Day 7: the late blastocysts “hatches: and settles onto the uterine wall
9. Implantation
a. The blastocysts settles on to the uterus at the embryonic pole
b. Implantation
i. Begins with attachment to the uterus (day 7)
ii. Ends when the blastocysts is completely embedded in the uterine wall (day 10)
iii. Only a small plug is visible on the uterine surface
c. Trophoblast (outer cell mass) cells contacting the uterus differentiate into syncytiotrophoblasts
i. Located at the embryonic pole
ii. In contact with the uterus
d. The remailing trophoblast are now called cytotrophoblast cells
i. Surrounding the blastocystic cavity
ii. Form a layer between the embryoblast and the syncytiotrophoblast

Lecture 7: Implantation and Fetal Membranes

1. Review: Blastocyst Attachment
a. The morula enters the uterus on day 4-5
b. The blastocoel forms on day 5-6
c. The blastocyst hatches on days 6-7
d. Before attachment the blastocyst consist of
i. Embryoblast
ii. Blastocoel
iii. Trophoblast cells
e. After attachment the trophoblast consists of
i. Syncytiotrophoblast
ii. Cytotrophoblast cells
2. Implantation
a. Trophoblast (outer cell mass) cells contact the uterus and differentiate into syncytiotrophoblast cells
i. Located at the embryonic pole
ii. In contact with the uterus
b. The remaining trophoblast are now called cytotrophoblast cells

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 i. Surround the blastocystic cavity and the embryoblast
ii. Form a layer between the embryoblast and the syncytiotrophoblast
c. The syncytiotrophoblast
i. Syncytiotrophoblast cells
1. Erode the uterine endometrium (uterine lining)
2. Grow into and proliferate (invade)
3. Forms a syncytium – multinucleated mass with no internal cell boundaries
ii. As the syncytiotrophoblast enlarges, the blastocyst is drawn deeper into the endometrium
iii. Syncytiotrophoblast cells keep differentiating as the blastocyst embeds until the blastocyst is completely
surrounded
iv. Cytotrophoblast cells divide to replace cells that differentiate into syncytiotrophoblast cells
v. Cytotrophoblast layer remain around the blastocystic cavity and over the embryoblast
vi. The blastocyst is less than 0.1mm on day 10
vii. Lacunae (spaces) from in the syncytiotrophoblast by day 10
1. Lacunae holes in swiss cheese
viii. By day 12, lacunae fuse into the lacunar networks
1. Connect to eroded maternal arteries and veins
2. Maternal blood begins to flow
3. Endometrial arteries  lacunar network  endometrial veins
ix. On day 13, primary chorionic villi form
1. Nubs on the cytotrophoblast
2. Extend into the lacunar network of the syncytiotrophoblast
3. Will develop into secondary and tertiary villi
3. Maternal Fetal Gas Exchange
a. Oxygen and nutrients form the maternal blood enter the lacunar networks and diffuse across the syncytiotrophoblast
and cytotrophoblast to supply the developing embryo. Carbon dioxide and metabolic wastes from the embryo diffuse
back into the maternal blood and are circulated back to the mother through the endometrial veins
i. There is NO mixing of maternal and fetal blood

4. Normal and Abnormal Implantation Sites

a. Normal implantation: body of the uterus
b. Abnormal implantation = ectopic pregnancy
i. 95% in the ampulla and the isthmus of the uterine tube
ii. Uterine tube ruptures by the 8th week
iii. Occur due to the scarring of the uterine tube
1. Pelvic inflammatory disease
2. Sexually transmitted disease
iv. Causes 40% of all female infertilities
v. Other abnormal sites possible
1. If fertilized on the fimbria, implantation on the ovary or abdominal cavity possible
a. Abdominal
i. Rectouterine pouch
ii. Mesenteries
vi. Order of frequency of ectopic pregnancies
1. Ampulla, isthmus, interstitial, infundibulum, abdominal, ovarian

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5. The embryo
a. Forms from the embryoblast
b. On day 7-8, the hypoblast forms
c. Remaining embryoblast is now the epiblast
6. The amnion
a. The amniotic cavity forms within epiblast
b. Divides epiblast into 2 layers of cells
c. Top cells thin, adhere to the cytotrophoblast layer and form the amniotic membrane
d. The base cells are thicker and adhere to the hypoblast layer
i. Together the epiblast + the hypoblast = the bilaminar embryonic disc
ii. Will form the embryo
7. The Yolk sac
a. Cells migrate from the edge of the hypoblast to line the cytotrophoblast layer
i. Called the exocoelomic membrane
b. Blastocoel cavity is now the primary yolk sac
i. Or exocoelomic cavity
ii. Or primary umbilical vesicle
c. Yolk sac
i. Provides nutrients for the embryo
ii. Forms blood cells
iii. Forms part of the gut
iv. Will be absorbed by the 11th week
8. Chorionic cavity
a. Cells differentiate from the exocoelomic membrane
b. Extraembryonic mesoderm forms between the cytotrophoblast cells and the yolk sac and amniotic cavity
i. Extraembryonic mesoderm splits to form the chorionic cavity between the two layers of mesoderm
1. Extraembryonic somatic mesoderm lines the cytotrophoblast and covers the amnion
2. Extraembryonic visceral mesoderm covers the primary yolk sac
9. Chorion
a. The chorion = extraembryonic somatic mesoderm + cytotrophoblast layer + syncytiotrophoblast layer
i. Will go on to form the placenta
b. The amnion and embryonic disc are connected to the chorion by a thick band of extraembryonic somatic mesoderm
called the connecting stalk
i. The stalk will eventually develop blood vessels and become the umbilical cord
10. Detecting Pregnancy
a. By the end of the second week the pregnancy can be detected
b. The large chorionic cavity can be observed on ultrasound
c. The syncytiotrophoblast cells produce a hormone called Human Chorionic Gonadotrophin or hCG. This hormone is
taken up in the mother’s blood and can be detected both in maternal blood and urine two weeks after conception
d. Home pregnancy tests detect whether hCG is present in the urine indicated an implanted pregnancy
i. At this stage the embryo is only 1 mm in size
11. Infertility
a. Infertility is a disease of the reproductive system defined by the failure to achieve a clinical pregnancy after 12 months
or more of regular unprotected sexual intercourse
b. Three primary causes of infertility
i. Male infertility
1. Low sperm count
2. Low sperm function
3. Malformed sperm
4. Endocrine
ii. Female infertility
1. Anovulatory
2. Immune response to conceptus
3. Anatomic
4. Hostile sperm environment
a. Chemical makeup of the uterus is not ideal

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 5. Endocrine
a. Can prevent ovulation
iii. Infertility because of the conceptus (Conceptus is the product of conception at any stage of development,
from fertilization to birth)
1. Genetic
2. Hatching abnormalities
3. Attachment abnormalities
4. Abnormal cell signaling
5. Poor trophoblast formation
6. Malformation
c. Frequency of abnormalities
i. Chromosomal abnormality 8%
ii. Genetics of conceptus 10%
iii. Endocrine factors 7%
iv. Uterine abnormalities 9%
v. Blood coagulation or platelet defect 28%
vi. Antiphospholipid antibody 19%
1. Caused blood clots and pregnancy loss
2. See with autoimmune diseases
vii. Other immune disorders and unknown 29%
d. 20-30% chance of clinical pregnancy each menstrual cycle (lower in infertile couples)
i. Clinical pregnancy: a confirmed pregnancy, a fetal hear beat can be detected
e. 70% of all conceptions are lost
i. Preimplantation: loss of conceptus before implantation
ii. Chemical pregnancy: loss of conceptus after implantation begins, but before heartbeat can be detected. hcG
test is positive
iii. Miscarriage: spontaneous loss of a conceptus before 20 weeks
iv. Stillbirth: loss of conceptus after 20 weeks
f. 30%
i. Live birth: a child born alive
ii. 60% of pregnancy are accidents
12. Review of Embryonic Tissues

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Lecture 8: Gastrulation and the Trilaminar Embryo
1. Review: The Bilaminar Embryo
a. Blastocyst with the embryoblast located at the embryonic pole
b. Embyroblast differentiates into the epiblast and the hypoblast
c. The amniotic cavity forms creating epiblast cells and the amniotic membrane
d. The epiblast layer + the hypoblast layer = the bilaminar embryonic disc
e. The exocoelemic membrane forms from hypoblast cell
f. Extraembryonic mesoderm forms between the exocoelomic membrane and the cytotrophoblast
g. The extraembryonic mesoderm splits
h. Extraembryonic somatic mesoderm covers the cytotrophoblat, amnion and embryonic disc
i. Extraembryonic visceral mesoderm covers the yolk sac
j. Chorionic cavity enlarges and the embryo + yolk sac are suspended by a thick connecting stalk of extraembryonic somatic
mesoderm
2. Gastrulation
a. Gastrulation: process by which the embryo goes from a bilaminar disc to a trilaminar disc
b. Epiplast cells divide and migrate to the midline, buckle inward and form a layer between the epiblast and hypoblast
c. This forms the primitive streak
i. Primitive groove – where cells dive down below the epiblast
ii. Primitive pit at the cranial end of the groove
iii. Primitive node ridge of tissue around the pit
d. The developmental fate is established during gastrulation
i. Pluripotent cells  more differentiated
e. Formation of the three primary germ layers – ectoderm, mesoderm, endoderm
f. All adult tissues are derived from these three embryonic germ layers
g. Gastrulation occurs throughout the 3rd week and tapers off late in the 4th week
h. Errors in gastrulation are predominately lethal, causing fetal or neonatal death due to sever malformation
i. Disrupted gastrulation affects entire body regions
i. The lower body (trunk and legs)
ii. Upper body (head, neck trunk)
j. Saccrococcygeal teratoma
i. when the primitive streak persists. Will form a solid or fluid filled tumor just behind the anus
k. Situs inversus
i. when the internal organs are reversed right to left. This is a mix up in the R – L orientation of the embryo which
happens during gastrulation
3. Formation of Germ layers
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 a. The first wave of cells replace the cells of the hypoblast layer and become endoderm
i. Endoderm will become the lining of the GI, respiratory, and urinary tracts, the tonsils, thymus, thyroid,
parathyroid, pancreas, and liver

b. The second wave of cells form a layer between the endoderm and the epiblast and become mesoderm
i. Mesoderm gives rise to muscle, cartilage, bone, connective tissue, heart muscle, blood vessels, blood cells,
kidneys, the gonads and lining of the body cavities
c. Cells remaining in the epiblast are now called ectoderm
i. Ectoderm gives rise to the nervous system, sensory organs, skin, glands in the skin, hair, nails and neural crest
tissue

4. Oropharyngeal and cloacal membranes

a. The mesoderm separates ectoderm form endoderm except at
i. Oropharyngeal membrane (or precordal plate) at the cranial end and will later become the mouth
ii. The cloacal membrane – at the caudal end and will later become the anus
b. These are the only places ectoderm and endoderm are directly opposed with no intervening mesoderm
5. Establishing the body axes
a. The morula is spherical: the body aces are not yet established
b. The dorsal – ventral axis of the embryo is set with formation of the blastocoel and embryoblast
c. The cranial caudal axis is established with formation of the primitive streak
d. The primitive streak forms at the caudal embryo
e. With both cranial – caudal and dorsal – ventral axis established, left and right can be identified
f. Body axis in the embryo are different than the adult
i. The embryo is C shaped
ii. The adult is upright and bipedal
1. Cranial – caudal = superior – inferior
2. Dorsal – ventral = posterior – anterior
6. Formation of the notochord
a. The first structure to form is the notochord
i. Formed from mesoderm cells passing through the primitive node
b. Steps of notochord formation
i. Mesoderm under the primitive nodes intercalate (mix with) the underlying endoderm
ii. A thin elongated notochordal plate forms in the endoderm
iii. The notochordal plate folds in on itself to make a tube
iv. The tube detaches from the endoderm
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 c. The notochord causes the surrounding tissues to differentiate
d. Overlying ectoderm  neural plate
i. The neural plate is a thickening of the ectoderm that will become the nervous system
e. Causes differentiation of the adjacent mesoderm
i. Paraxial mesoderm
1. Closest to the notochord, becomes bones and muscles of the trunk and limbs
ii. Intermediate mesoderm
1. Further from the notochord, becomes urinary and reproductive system
iii. Lateral mesoderm
1. Furthers from the notochord, becomes the body cavities, muscles of the GI system, and anterior body
wall
f. Later in development, the notochord becomes the nucleus pulpossus of each intervertebral disk

Lecture 9: Early Embryo: Weeks 3 and 4

1. Review: Gastrulation and Notochord
a. Gastrulation
i. Identifies cranial-caudal, and L-R body axes
ii. Creates the trilaminar embryo
iii. Forms ectoderm, mesoderm, and endoderm
b. Notochord
i. Mesoderm formed at the primitive node becomes the notochordal plate in the endoderm. The notochordal
plate infolds and detaches from the endoderm to form the notochord
ii. The notochord functions to differentiate surrounding tissues
iii. Ectoderm  neural plate  nervous system
iv. Mesoderm  paraxial, intermediate and lateral
2. Nurulation: formation of the nervous system
a. Neurulation begins middle of the 3rd week, ~day 17
b. The notochord induces ectoderm  neuroectoderm  neural plate
i. Neural plate is thicker, will form the nervous system
ii. First organ system to begin forming
c. Cells in the neural plate proliferate
d. Edges elevate into neural folds
i. The folds bend toward each other
ii. The folds fuse forming the neural tube
e. The neural tube separates from the ectoderm
f. Fusion begins in the cervical region day 20-21
g. Fuses both cranial and caudally
h. The tube is open at both ends
i. The cranial neuroprore closes around day 25
ii. The caudal neuroprore closes around day 27
1. The cranial region becomes the brain , the remainder becomes the spinal cord
i. Neural tube defects: second most common birth defect
i. Severe
1. Anencephaly and spina bifida when the cranial vault or spinal canal did not close. Underlying nervous
tissue is exposed
ii. Mild
1. Spina bifida occulta no lesion externally but a defect in vertebral arch formation can be seen on
radiographs
3. Neural crest
a. Neural crest originates in the ectoderm on the lateral edge of the neural plate
b. Moves with the elevating neural fold
c. Migrates into the mesoderm between the neural tube and overlying ectoderm

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 d. Separates and migrates on either side of the neural tube
e. Neural crest derived structures
i. Often regarded as a 4th germ layer
1. Pigment cells in the skin and hair
2. Peripheral sympathetic nervous system
3. Glial cells (supportive cells) in the nervous system
4. Meninges around the brain and spinal cord
5. Teeth and bones of the face
6. Cartilages of the larynx
7. Structures in the eye and ear
8. Glands: thymus, thyroid, pituitary, salivary
9. Cells of the adrenal medulla
10. Outflow track of the heart
ii. Because so many structures are derived from neural crest tissue,
teratogens, that affect neural crest formation or migration, can have
profound and devastating effects on developing embryo

4. Mesoderm
a. The final fate of the mesoderm cells depends on where they pass through the
primitive streak
b. From cranial (primitive node)  caudal (cloacal membrane)
i. Notochord
ii. Paraxial mesoderm
iii. Intermediate mesoderm
iv. Lateral mesoderm
v. Extraembryonic mesoderm
c. Need signals from the notochord to differentiate
d. Mesoderm derivatives
i. Paraxial mesoderm will form somites
1. Paraxial mesoderm coalesces into paired blocks on either side of the notochord and developing neural
tube
2. Somitomeres smaller, found in the head region
a. Cells migrate to the pharyngeal arches and face
3. Somites larger, found in the neck and trunk region
a. Cells migrate to form the body wall and limbs
b. Form at regular intervals from cranial to caudal
i. Day 20 (end of 3rd week: being forming)
ii. Day 34 (end of 5th week) finished forming ~ 42 to 44 pairs
c. Formed by cyclical expression of cell signaling and growth factor genes
d. Components of somites
i. Sclerotome: ventromedial portion – forms: vertebra and ribs
ii. Dermotome: lateral portion – forms: the deep layer of the skin (dermis) of the back
and limbs
iii. Myotome: dorsomedial and ventrolateral to the dermatome but migrate under the
dermatome to form a single layer – forms: muscles of the back and limbs
iv. Each segment forms an association of nerve, muscle and skin that remains linked
ii. Intermediate mesoderm forms urinary and reproductive tracts
1. Intermediate mesoderm divides to form the urogenital ridge
2. The urogenital ridge differentiates into two regions that will form
a. Urinary system: kidneys and the ureter (the bladder develops from the allantois not
intermediate mesoderm)
b. Reproductive system: gonads (ovaries and testicles) and the ducts leading from the gonad to
the external reproductive organs
iii. Lateral mesoderm forms the body wall, limbs, and the muscular layers and blood vessels of the internal organs
1. Lateral mesoderm splits:
a. Parietal (or somatic) lateral mesoderm is continuous with somatic extraembryonic mesoderm

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 i. Abdominal wall and limbs, linings of the body cavity wall
b. Visceral *or splanchnic) lateral mesoderm is continuous with visceral extraembryonic
mesoderm
i. Muscular layers and blood vessels of the gut, external covering of the internal organs
c. How does the mesoderm form all of this?
i. Abdominal wall
ii. Limbs
iii. Linings of the body cavity
iv. Muscular layers of the gut
v. Blood vessels of the gut
vi. External covering of all the internal organs
1. Embryo folding
5. Embryo folding
a. Transition from a flat trilaminar disk into a hollow tubular embryo
b. Folds in two directions
i. Cranio-caudal from growth of the nervous system
ii. Lateral from growth of somites
c. Results from unequal proliferation of cells on the upper surface of the embryonic disk
d. Starts at the beginning of the 4th week
e. Ends at the end of the 4th week
f. Cranial folding
i. Causes the oropharyngeal membrane (mouth) and cardiogenic region (heart) to be ventral to the nervous
system
ii. Causes the cardiogenic region to be caudal to the oropharyngeal membrane and located in the chest region
iii. Creates the foregut which is now lined with endoderm

g. Caudal folding
i. Causes the primitive streak to be caudal to the cloacal membrane (anus)
ii. Causes the allantois, (an early fetal membrane that will form the urinary bladder) and the connective stalk
(umbilical cord) to be located on the ventral surface
iii. Creates the hindgut which is now lined with endoderm
1. Ends with the cloacal membrane  anus and openings of the reproductive and urinary tracts

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 h. Lateral folding, lateral mesoderm and the body wall
i. Parietal (somatic) lateral mesoderm + ectoderm  body wall
1. Forms: the body wall, limbs, membranous lining on inside of the body cavity
ii. Separates the body cavity from the chorionic cavity
i. Lateral folding, lateral mesoderm and the GI tract
i. Visceral (splanchnic) lateral mesoderm + endoderm  gut
1. Forms the muscles of the gut, mesenteries, and membranous coverings of the gut
ii. Decrease yolk sac size
iii. Pull the amniotic membrane around the embryo enclosing it in the amniotic cavity
iv. Cover the connecting stalk (future umbilical cord) with amnion
j. Malformation of the body wall
i. Failure in closure of the body wall
ii. Thoracic wall defect
1. Ectopia cordis the heart located outside the body wall
iii. Abdominal wall defect
1. Gastroschisis loops of intestine or other organs are located outside the body
2. Exstrophy of the bladder the bladder is located outside the body wall

Lecture 10: Early Embryo: Weeks 4 to 8

1. Review: The 3rd and 4th week
a. Gastrulation continues
b. The neural tube forms
c. Neural crest forms and begins to migrate
d. Mesoderm differentiates
e. Somites form
f. The embryo folds
2. Pharyngeal arches
a. The pharyngeal apparatus forms over the 4th to 5th week. Six pairs of arches form sequentially (cranial caudal) in the
neck region of the embryo
b. The arches are numbered 1 to 6; however, arch 5 is rudimentary or absent
c. Externally the arches are separated from each other by grooves called pharyngeal grooves or pharyngeal clefts
d. Internally inside the developing pharynx, the arches are separated by grooves called pharyngeal pouches. These grow
toward the pharyngeal clefts
e. The pharyngeal clefts on the outside and pharyngeal pouches on the inside come close to each other but they never
perforate into an opening
f. Because the clefts and pouches never perforate, a pharyngeal membrane composed of ectoderm a thin layer of
mesoderm and endoderm remains between the arches

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 g. In the 4th week, tissue migrates from adjacent somitomeres
i. Neural crest – to form bone, tendon and connective tissue
ii. Mesoderm – to form muscle and blood vessels
iii. Cranial nerve – to innervate muscle
h. Each arch is now composed of the following
i. A supporting cartilaginous rod
ii. A muscular core
iii. Sensory and motor nerves that supply the mucosa and muscles of each arch
iv. A pharyngeal arch artery that connect the heart with the aorta
i. In the 5th week, the 2nd pharyngeal arch overgrows the 3rd and 4th arches creating a pocket called the cervical sinus
j. The cervical sinus usually disappears in the 7th week as the arches grow together smoothing out the neck contour
k. If the cervical sinus persists, it can form a cervical sinus cyst. The cyst remains open to the surface or pharynx it is called
a branchial fistula. Cervical sinus cysts are usually located anterior to the sternocleidomastoid muscle

l. Arch syndromes
i. Result from decreased or impaired neural crest
ii. First arch syndromes are associated with structures derived from the first pharyngeal arch. Second arch
syndromes are associated with structures derived from the second arch etc. All arise from the same underlying
cause
iii. Multiple arches may be affected depending on the time of exposure
iv. First and second arch syndromes often occur together
1. Unilateral or bilateral
2. Associated with facial clefting, hearing loss, small malformed facial bones and muscles
v. Examples of first arch syndrome include: Goldenhar’s syndrome, Treacher Collins Syndrome, DiGeorge
Syndrome
3. Body cavities
a. The early body cavity intraembryonic coelom forms over the 4th to 11th week
b. It forms from the space created when the lateral mesoderm splits into parietal and visceral layers
c. The space is continuous with the chorionic cavity (extraembryonic coelom and forms as a U shape around embryonic
disk

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 d. Embryo folding:
i. Brings together the body folds from each side
ii. Separates the intraembryonic coelom from the extraembryonic coelom (chorionic cavity)
e. Fusion of the ventral body wall isolates the coelomic (body cavity) space
f. Parietal lateral mesoderm
i. Forms: the body wall, membranous lining on inside of the body cavity
g. Visceral lateral mesoderm
i. Covers the gut (foregut, hindgut) and yolk sac
ii. Forms the muscles of the gut, mesenteries, and membranous coverings of the gut
h. Yolk sac
i. Protrudes into the chorionic cavity
ii. Decreases in size
iii. Incorporates into the midgut
iv. Is gone by 11 weeks when the body wall closes
4. Digestive system
a. The foregut and the hindgut are formed in the 4th week from embryo folding and are lined with endoderm from the yolk
sac
i. The foregut terminates with the oropharyngeal membrane  mouth
ii. The hindgut terminates with the cloacal membrane  anus
b. The midgut is lined with embryonic endoderm and is open to the yolk sac
i. Yolk sac protrudes into the chorionic cavity
ii. Incorporated into the midgut by 11 weeks
5. The cardiovascular system
a. Early heart develops late in the 3rd week
b. First organ system to become functional
c. Endocardial tubes develop in the cardiogenic region
d. This primordial heart joins with newly formed blood vessels
i. Yolk sac  vitelline vessels
ii. Umbilical  umbilical vessels
iii. The embryo  major vessels (aorta, vena cava)
e. The heart begins to beat day 21-22
f. Vasculogenesis
i. Aggregation of angioblasts (vessels forming cells) into blood islands
ii. Differentiation of angioblasts into endothelial cells
iii. Blood islands coalesce to form the major blood vessels
g. Angiogenesis
i. Sprouting of new vessels off preexisting vessels
h. Hematopoiesis
i. Formation of blood cells
ii. Begins in the 3rd week
iii. From endothelial cells in blood islands
iv. Begins in the Yolk sac  liver  thymus  spleen  bone marrow
v. Embryonic, fetal and adult erythrocytes are formed from different progenitor cells
vi. Fetal erythrocytes are present from 6-7 months after birth
6. Staging embryonic development
a. Classification based on embryonic events
i. Preimplannation = week 1
ii. Bilaminar disk = week 2
iii. Trilaminar disk = week 3
iv. The embryonic period = 3rd – 8th week
v. The fetal period = 9th week to birth
b. Based on morphology
i. The Carnegie system uses standardized morphological features that can be observed and used to accurately
stage and compare developmental progression
ii. It is based on clearly observable or measurable physical features
c. Based on time

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 i. Months
1. Gestation is divided into 9 months, and 3 trimesters
2. Used by public at large
ii. Embryonic age: measured from fertilization onward
1. This is the most accurate way to describe development
2. Used by embryologists
3. Clinically not so useful – can’t determine exact time of fertilization
4. Also called fertilization age or postovulatory age
iii. Gestational age: estimates embryo age based on the woman’s last menstrual period
1. Widely used clinically due to ease of measurement
2. Inaccurate for women with long or short cycles
3. Inaccurate for women with irregular cycles or hormonal birth control
4. Counting begins before fertilization

Lecture 11: Development of Bone and Muscle I

Development of the axial skeleton timeline

1. Review: The 3 to 4 week embryo

a. Over the 3rd to 4th week
i. Gastrulation occurs. Mesoderm forms as cells migrate through the primitive streak
ii. Somites form and differentiate
iii. The neural plate thickens, neural folds elevate and then fuse to form the neural tube
iv. Neural crest migrates into a cluster located on either side of the neural tube
v. The embryo elongates and folds, changing from a flat disk into a tubular shape
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 vi. Pharyngeal arches form
vii. The heart forms and begins to beat
viii. Limb buds
b. Gastrulation and notochord
i. Gastrulation: invagination of cells through the primitive streak
1. Established the cranial-caudal, and L-R body axes
2. Creates a trilaminar embryo
3. Differentiates tissues into ectoderm, mesoderm, and endoderm
ii. Notochord formation
1. Mesoderm cells that invaginate at the primitive node will intercalate with the newly forming
endoderm. These mesoderm cells grow cranially forming an elongated notochordal plate
2. The notochordal plate then infolds to form a tubular structure, the notochord
3. The notochord pinches off from the endoderm leaving a continuous layer of endoderm underlying the
mesoderm derived notochord
c. Mesoderm derivatives
i. The notochord induces differentiation of mesoderm on either side to form paraxial mesoderm (close to the
notchord) intermediate mesoderm and lateral mesoderm
ii. The paraxial mesoderm will form somites
iii. The intermediate mesoderm forms structures associated with the urogenital tract
iv. The lateral mesoderm splits into two layers
1. The somatic (or parietal) mesoderm is continuous with extraembryonic mesoderm covering the
amnion and forms the dermis of the sides, abdominal wall and limbs, and the serosal linings of the body
cavity
2. The visceral (or splanchnic) mesoderm is continuous with extraembryonic mesoderm covering the yolk
sac and forms the muscular layers of the gut, and the serosal covering of the gut
2. Formation of somites
a. Paraxial mesoderm differentiates into chunk like segments called somites located on either side of the neural tube
b. Somites form at regular intervals from cranial to caudal
c. Mesoderm in the somites will differentiate into 3 components called sclerotome, dermatome and myotome
i. Sclerotome -forms in the ventromedial portion of the somite and will become the vertebrae
ii. Dermatome – forms in the lateral portion of the somite. The mesoderm differentiates into fibroblasts that will
become the dermis (deep layer of skin) of the back and body wall
iii. Myotome – forms in two locations within each somite: dorsomedial and ventrolateral. The two clusters expand
and will fuse under the dermatome to form the muscles of the back and body wall
d. Neural crest differentiates into a cluster of nerve cell bodies in each somite
i. These cell bodies connect to sensory structures in the dermatome and also send processes into the developing
neural tube.
1. This allows sensory nerve impulses to be transmitted to the central nervous system
ii. Spinal nerves grow out of the neural tube into each somite to innervate the myotome.
1. This allows motor nerve (for movement) impulses to be transmitted to the muscles
iii. Within each somite, the sclerotome splits into cranial and caudal portions to allow access of these developing
spinal nerves to the myotome and dermatome
e. Each somite forms an interconnected assembly of bone (vertebra and rib) nerve, muscle, and skin. As the embryo grows,
these structures remain associated and connected throughout development
f. Large visible somites form in the neck and trunk region
g. Smaller less visible somitomeres are found in the head region
i. Tissues within these segmented structures grow, migrate, and differentiate to form the musculoskeletal system
of the whole body
3. Formation of bone: Intramembranous ossification
a. Bone forms by two mechanisms: intramembranous ossification and endochondral ossification
b. Intramembrous ossification occurs in the flat bones of the face and head. Mesenchyme (undifferentiated mesoderm or
neural crest) aggregates into flat membranous sheets; and then cells differentiate into osteoblasts
c. Osteoblasts create an unmineralized extracellular matrix called osteoid.
i. The osteoid becomes mineralized and traps the osteoblasts in the developing bone.
ii. Osteoblasts are now called osteocytes
d. The following bones are formed by intramembranous ossification

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 i. Frontal, parietal, squamous part of the temporal bone, mandible, maxillae, palatine, zygomatic, and nasal
4. Formation of bone: endochondral ossification
a. In endochondral ossification, a cartilage model of the bone is formed first. This model is covered by a thin membrane
called the perichondrium
b. The cartilage then begins to mineralize to form bone.
i. Mineralization occurs first in the diaphysis under the perichondrium.
1. The perichondrium becomes the periosteum as bone forms
c. Secondary ossification centers form in the epiphyses of the long bones
d. Growth of the bone occurs by deposition of new cartilage at the physis or growth plate located between the diaphysis
and the epiphysis. The new cartilage is mineralized by osteoblasts to elongate the diaphysis and moves the growth plate
distally
e. The inner region of the bone vascularizes and forms bone marrow the site of red blood cell production
f. The following bones are formed by endochondral ossification
i. Ethmoid, sphenoid, petrous and mastoid parts of the temporal, basilar part of the occipital, hyoid, limb bones,
vertebrae, sternum, ribs
5. Formation of joints
a. Joints develop in the 6th to 8th week
b. There are three kinds of joints
i. Fibrous, cartilaginous, and synovial.
ii. All begin with the formation of interzonal mesenchyme between two adjacent bones
1. Fibrous joints form when the interzonal mesenchyme differentiates into fibroblasts which form a
dense fibrous connective tissue connecting the two bones (eg joints between skull bones)
2. Cartilaginous joints form when the interzonal mesenchyme differentiates into either hyaline cartilage
(costochondral joints) or fibrocartilage (pubic symphysis)
3. Synovial joints form when a cavity develops in the interzonal mesenchyme creating the joint space
(joint cavity). The outer layer of interzonal mesenchyme thickens to form the dense outer joint capsule
and ligaments. Mesenchyme lining the joint space differentiates into synovial membrane
6. Formation of vertebrae
a. In the 4th week, sclerotome mesoderm migrates medially to surround both the notochord and the neural tube. This
established the mesenchyme that will form the vertebrae
i. The mesenchyme surrounding the neural tube will form the vertebral arches including the pedicle, lamina,
spinous process, transverse process and articular process
ii. Mesenchyme surrounding the notochord will become the vertebral body
iii. In each somite, a small projection of mesenchyme called the costal process forms/ In the thoracic region it will
grow laterally into the body wall and will become ribs
b. Splitting of the sclerotome and formation of the vertebral body
i. In each segment, the ventral component of sclerotome mesenchyme around the notochord differentiates to
form a band of loosely packed cells cranially and another band of densely packed cells caudally
ii. The densely bands split into cranial and caudal portions
1. The cranial portion of the dense band becomes the intervertebral disc
2. The caudal portion of the densely packed band fuses with the loosely packed mesenchyme of the next
caudal sclerotome to form the vertebral body. Thus, each vertebral body forms as an intersegmental
structure from the sclerotomes of two adjacent somites
3. Splitting of the sclerotome in each segment is necessary to provide an opening route for the spinal
nerve to innervate the myotome
c. In the 5th week, the sclerotome differentiates and splits
d. The notochord disintegrates except for portions in each intervertebral disc. The remains of the notochord becomes the
nucleus pulposus of each disc
e. In the 6th week, chondrification centers form in the vertebral mesenchyme. These are localized areas where
mesenchyme differentiates into chondrocytes. Chondrocytes begin to form cartilage, creating model of the bone
f. Late in the 7th week, ossification centers begin to form in vertebral body, thus the vertebrae form by endochondral
ossification
g. In the 8th week, ossification centers form in the vertebral arches
h. At birth, the majority of vertebrae is ossified
i. The apex of the vertebral arch and connection to the centrum remains cartilaginous to allow for continued
growth

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 i. Between 3-5 years of age, the left and right vertebral arches will fuse with each other and with the vertebral body
j. Secondary ossification centers appear in the vertebra after puberty at the tips of the spinous and transverse processes,
and in rim around the centrum of the body

k. Malformations of Vertebrae
i. Spina bifida
1. Result of a neural tube defect. With spina bifida; the lamina and or pedicles do not form.
a. Spina bifida occulta: The vertebral canal may be covered by skin
b. Spina bifida: the vertebral canal is open to the environment
ii. Spondylolisthesis
1. Occurs when the ossification centers in the pedicles do not fuse with the body or centrum of the
vertebra
2. Usually occurs at L5-S1 and results in lordosis as the affected vertebral body slips anterior
iii. Hemivertebra
1. Results when only one chondrification center forms in the vertebral body. Since there is only 1
chondrification center, only half of the vertebral goes on to form bone, the other half vertebral body
half can not form bone as there is not cartilage model.
a. This creates a wedge shaped vertebrae and results in scoliosis
7. Formation of Ribs
a. The sclerotome mesenchyme forms a small lateral projection called the costal process on every vertebra
i. The costal processes in the thoracic region grow laterally into the body wall to form ribs. Costal processes in
other regions regresses
b. Ribs are ossified during the fetal period
c. The rib attachment to the vertebra develops as a synovial costovertebral joint
d. Malformation of ribs
i. Malformations of the ribs are relatively common
1. Malformations include
a. Variation in rib number
b. Variation in attachment site
c. Fused ribs
d. Variation in the rib attachment will give rise to abnormal numbers of true, false and floating
ribs
2. Accessory ribs or supernumerary ribs are most commonly found on L1 and are called lumbar ribs.
Lumbar ribs usually do not cause clinical symptoms
a. 1% or 1 in 100
3. Accessory ribs are less commonly found on C7 where they are called cervical ribs. In this location, they
can compress vascular and nerve elements
a. 0.6% or 1 in 150
4. Accessory ribs are usually rudimentary
5. Rib malformations are a result of abnormal segmentation and formation of somites

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8. Formation of the sternum
a. The sternum develops from two mesenchyme bars called sternal bars that develop from lateral plate somatic mesoderm
b. As the body wall ventral body wall closes, the two sternal bars come together and fuse to form the manubrium, body
and xiphoid process in week 8
c. The mesenchyme differentiates into cartilage and joins with cartilage precursors of the costal cartilages
d. Chondrification centers form in the mesenchyme. Those in the body are segmented and are called sternabrae
e. Ossification centers form in the cartilage model. Ossification is mostly complete before birth, except for xiphoid which
ossifies in childhood
f. Malformations of the sternum
i. If the sternal bars do not fuse, or if fusion is incomplete, a cleft sternum results
ii. Small clefts are usually of minimal clinical significance
iii. Pectus excavatum
1. Displacement of the sternum dorsally (posteriorally) causing a concave depression in the chest
iv. Pectus excavatum
1. Thought to be caused by increased ventral growth of the costal cartilages displacing the sternum
dorsally (posteriorally)
9. Formation of the cranium
a. The cranium can be divided into two components: the neurocranium (bones encasing the brain) and viscerocranium
(bones of the face)
i. Neurocranium: develops from cranial neural crest mesenchyme and paraxial mesoderm.
1. The neurocranium increase in size up to 2 years due to rapid growth of the brain. After this time, there
is slower enlargement of the cranium up to adulthood
ii. Viscerocranium: develops from neural crest mesenchyme in the pharyngeal arches
b. Following bones are formed by endochondrial ossification
i. Ethmoid, sphenoid, petrous, and mastoid of the temporal, and basilar part of the occipital
c. Following bones are formed by intramembranous ossification
i. Frontal parietal, squamous part of the temporal bone, mandible, maxilla, palatine, zygomatic and nasal
d. The face changes in size and shape until adulthood due to formation and eruption of the teeth, and growth of the
paranasal sinuses
e. Formation of the sutures and fontanelles
i. During developing the flat bones of the skull are separated by dense fibrous connective tissues (fibrous joints)
called sutures
ii. Sutures remain open to allow growth of the cranium in childhood; sutures fuse later in adulthood
1. There are 5 sutures: frontal, sagittal, lambdoid, coronal, squamous
iii. Fontanelles are large fibrous areas where several sutures meet
1. There are 6 fontanelles, unpaired anterior, posterior, and paired sphenoid, and mastoid
2. All fontanelles close after birth
a. The sphenoid and posterior fontanelles close at 6 months of age
b. The anterior and mastoid fontanelles close at 2 years of age
f. Malformations of the cranium
i. Premature closure of a suture, called craniosynostosis, prevents further growth at that suture and results in
abnormalities of skull shape.
ii. The following are caused by premature closure:
1. Oxycephaly: premature closure of the lambdoid and coronal sutures, results in lower shaped head
2. Plagiocephaly: premature closure of the lambdoid and coronal sutures on one side of the head
3. Brachycephaly: premature closure of the coronal suture, results in square shaped head
4. Scaphocephaly: premature closure of the sagittal suture and results in a wedge shaped head
5. Microcephaly: is characterized by small head and is associated with early closure of the sutures, but
the defect is a result of abnormal brain development, not craniosynostosis
10. Development of the axial skeleton timeline

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Lecture 12: Embryology of Bone and Muscle II
1. Review
a. Mesoderm Differentiation
i. Paraxial – will become somite
ii. Intermediate – will become the urinary and reproductive tracts
iii. Lateral – splits into two layers
1. Parietal (or somatic) lateral mesoderm will become muscles of the body wall and bones of the limbs
2. Visceral (or splanchnic) lateral mesoderm will become the muscles of the GI tract
b. Somite formation
i. Sclerotome – will become the vertebrae
ii. Dermatome – will become the dermis of the back and body wall
iii. Myotome – forms in two clusters. Will become muscles of the back, limbs, and body wall
iv. Neural crest – differentiates into nerve cells that innervate the dermatome
v. Spinal nerves – innervate the myotome
2. Development of muscle and limbs
a. Development of the musculoskeletal system gives us our final form and shape
b. The musculoskeletal system is derived from mesoderm and neural crest
3. Formation of muscle
a. Most muscles are formed before birth, a few muscles are formed the first year of life
b. Concentrations of mesenchyme from mesoderm or neural crest origin migrate to the appropriate location. The
mesenchyme differentiates into myoblasts. Groups of myoblasts then split into discrete bundles that can be
distinguished as individual muscles. Myoblasts mature into muscle cells
i. Once formed, the muscle cells do not divide. Muscles increase in length and width by increasing the number of
myofilaments in each cell
ii. Muscles increase in length and width with childhood growth and also with use/exercise
c. There are three kinds of muscles
i. Skeletal (striated) muscle
1. Derived from myotomes located in the head and trunk
2. Also derived from lateral mesoderm
3. Forms all voluntary muscle of the face, neck, back, limbs, and body wall
ii. Smooth muscle
1. Derived from visceral lateral mesoderm surrounding the gut tube – forms muscles in the gut
2. Also derived from somatic mesoderm – forms smooth muscle in the walls of the blood vessels
3. Also derived from ectoderm – forming the smooth muscle found in sweat and mammary glands
iii. Cardiac muscle
1. Derived from visceral mesoderm surrounding the heart tube – forms the heart
4. Dermatomes
a. Develops from the lateral component of paraxial mesoderm in each somite
i. Will become the deep layer of the skin, the dermis
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 b. Represents an area of the skin innervated by one spinal nerve
i. As the embryo grows, the dermatome stays associated with that spinal nerve
ii. Can map on the body surface the areas associated with each spinal nerve
iii. Marks tissue originating in individual somites
5. Myotomes
a. Myotomes are derived from paraxial mesoderm that differentiate into muscle. Each myotome segment is innervated
by one spinal nerve
b. The myotome retains its segmented pattern in the early embryo much like the dermatomes
i. Some muscles remain segmented (intercostal muscles, serratus muscles)
ii. Most muscle cells migrate out of the myotome and form nonsegmented muscles
iii. They still retain their segmented innervation by the spinal nerve
6. Muscles of the body wall
a. The myotome originates as two clusters of cells
i. Dorsomedial and ventrolateral to the dermatome
ii. The myotome clusters become contiguous but remains as two distinct populations
iii. The dorsomedial cluster becomes the epimere
iv. The ventrolateral cluster becomes the hypomere
b. The hypomere muscle fibers intermix with muscle fibers in the parietal lateral mesoderm to create the muscles of the
anterior body wall
c. Spinal nerves comes off the neural tube at each segment and pass through the split sclerotome
d. The spinal nerves has 2 branches
i. The dorsal ramus (branch) innervates the epimere
1. Muscles differentiating from the epimere are called epaxial muscles
a. The form the extensors of the head, neck, and back: the erector spinae group
b. All are innervated by the dorsal ramus of the spinal nerve
ii. The ventral ramus (branch) innervates the hypomere
1. Muscles differentiating in the hypomere are called hypaxial muscles
a. They from the flexors of the head, neck, and back, the intercostal, abdominal, serratus,
quadratus lumborum, pelvic floor and limb muscles
b. All are innervated by the ventral ramus of the spinal nerve
e. Malformations of trunk musculature
i. Partial or complete absence of a muscle is relatively common and usually not debilitating
1. Examples include palmaris longus, serratus anterior, quadratus femoris, pectoralis major and the
sternal head of pectoralis major
ii. Absent or poorly formed abdominal wall muscles called Prune Belly Syndrome. It occurs in 1 in 30,000 live
births.
1. Males are affected 20 times more often than females
2. Prune belly syndrome is associated with reproductive and urinary tract malformations. Fluid
accumulates in the abdomen causing a distended abdomen. Disruptions in mesoderm differentiation
between weeks 4-6 is thought to be the cause
7. Muscles of the head
a. Eye muscles
i. Mesenchyme from myotomes located in the head somitomeres will form the muscles that control movement
of the eyes
b. Muscles of the face
i. Neural crest tissue in the occipital somitomeres of the head migrate into the developing pharyngeal arches
late in the 4th week
ii. This neural crest derived mesenchyme in the pharyngeal arches will give rise to all the facial muscles
iii. Each arch has been associated cranial nerve that innervates muscle derived from that arch
8. Formation of the limb buds
a. During the 4th and 5th wee buds of tissue appear on the sides of the embryo in cervical and sacral regions.
i. These are called limb buds and will form the limbs
b. Parietal lateral mesoderm migrates into the newly forming limb buds and creates a central core.
i. This mesenchyme will eventually form the skeletal and vascular components of the limbs
c. Dermatome and myotome mesenchyme from the cervical and sacral somites also migrate into the limb buds. The
myotome elements form two condensations in each bud.

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 i. These condensations will become muscles in the limb
d. The leading edge of the limb bud forms a ride of epithelium (ectoderm) called the apical ectodermal ridge. This ridge
secretes a number of growth factors which drives and coordinates development and differentiation of the limb
9. Formation of the upper limb
a. Upper limb buds form by day 26-27
b. Lateral mesoderm migrates into the limb bud late in the 4th week
c. Somitic mesoderm (myotome) migrates into the limb bud forming anterior and posterior condensations in the 5th
week
i. The posterior condensation gives rise to the extensor and supinator muscles
ii. The anterior condensation gives rise to the flexor and the pronator muscles
d. The ventral rami of spinal nerves C5 to T1 combine into trunks, which then divide into anterior and posterior divisions
i. The anterior division nerves innervate the anterior condensation
ii. The posterior division nerves innervate the posterior condensation
e. The dermatome from each somite migrates into the limb along with the myotome. The spinal nerve for each somite
innervates the dermatome creating a segmented pattern on the skin
10. Formation of the lower limb
a. Lower limb buds form by day 30-31
b. In the 5th week, both lateral mesoderm and somatic (myotome) mesoderm migrate into the limb bud
i. The posterior condensation gives rise to the extensor and ABductor muscles
ii. The anterior condensation gives rise to the flexor and ADductor muscles
c. The ventral rami of spinal nerves L2-S3 divide into anterior and posterior divisions as they enter the limb bud
i. The anterior division nerves innervate the anterior condensation
ii. The posterior division nerves innervate the posterior condensation
d. The dermatome migrates as well, creating characteristics innervation patterns on the skin
11. Bones of the limb
a. In the limb bud, the mesenchyme core (from the lateral mesoderm) condenses to form soft primordial bones over
weeks 5-6
b. Chondrification centers appear in the primordial bones during week 6
c. Ossification centers appear in the cartilage models of the bone by week 7
i. The clavicle is the first bone to ossify; some bones (eg carpal bones) are not ossified until after birth
d. Bone growth continues at the growth plate (physis or epiphyseal plate). Bones are not completely ossified until the
growth plate closes
e. Hands and feet
i. Handplates develop in the upper limb buds in week 6 and footplates develop in the lower limb week 7
ii. Condensations of mesenchyme called digit rays form in the hand and footplates late in the 6th and 7th week
respectively
iii. The mesenchyme between the digit rays breaks down by apoptosis delineating the fingers and toes
f. Regionalization of limbs
i. The apical ectodermal ridge (AER) at the tip of the limb bud drives limb differentiation by secreting growth
and differentiation factors
ii. These growth factors cause the limb to differentiate into the different regions (arm, forearm, wrist, hand) as
the limb elongates
iii. At the base of the AER is the ZPA (zone of polarizing activity). This region secretes factors that differentiate
the limb in the anterior posterior axis such that the digits appear in the proper sequence
g. Malformations of the limb
i. The most critical period for limb development is between 24 to 36 days post fertilization. This is when the limb
buds are forming and the developing limb is most sensitive to teratogenic insult
ii. Malformations of both bone and muscle
1. Amelia: absence of the limb
2. Meromelia: absence of part of a limb, or presence of a limb stump
a. Both amelia and meromelia can be caused by genetics and or environmental factors. The
best known cause of these malformations is exposure to the drug thalidomide
iii. Malformation of muscle only
1. Congenital joint contracture or arhtyrogryposis
a. This condition is caused by muscle hypoplasia and or the absence of muscle. This causes
stiffness and contraction across joints

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 h. Malformations of the digits
i. Malformations of the digits include
1. Syndactyly: a reduction in digits caused by incomplete separation of the digits.
a. Can either by cutaneous – incomplete apoptosis of the webbing between the digits
b. Or osseous - fusion of the digital bones
2. Cleft hand or foot: a variety of syndactyly where five digit rays do not form usually affects 2 nd, 3rd,
and 4th digits
3. Polydactyly: supernumerary digits, results from the formation of extra digit rays during early
formation of the limb
ii. Amniotic band syndrome
1. Bands of amniotic membrane occasionally detach and float free in the amniotic cavity. The tissue may
wrap around digits or limbs cutting off circulation. The distal portions of digits or limbs die and
regress
2. This is not a malformation resulting from abnormal formation or growth of limbs or digits
12. Clinical case: Cervical rib review on slide 23
13. Development of muscle and limb timelines

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