Early Human Development - Block II

Second Week Of Development

I. Implantation
A. 2nd Week: Implantation is completed
B. As the blastocyst implants, more trophoblast contacts the endometrium and differentiates into 2 Layers: QUIZ 2
15 Questions: 9 From Dr. Mishra
1. Cytotrophoblast 6 From Dr. Z
2. Syncytiotrophoblast
a) Invades the endometrial connective tissue
b) The blastocyst slowly becomes imbedded in the endometrium
c) Syncitiotrophoblastic cells displace the endometrial cells at the implantation site.
(1) The endometrial cells undergo apoptosis to facilitate the invasion.
d) B/w Days 6 - 9: embryo fully implanted in the endometrium.
(1) The syncytiotrophoblast covers the entire blastocyst, EXCEPT for a small region at the abembryonic pole.
(2) The coagulation plug seals the small hole where the blastocyst implanted
(3) The Syncytiotrophoblast produces a glycoprotein hormone, human chorionic gonadotrophin (hCG), which enters the
maternal blood via isolated cavities (lacunae) in the syncytiotrophoblast
(a) hCG maintains the hormonal activity of the corpus lute in the ovary during pregnancy.

II. Embryoblast Reorganization

A. Cells of the embryoblast differentiate into 2 Epithelial Layers:
1. Epiblast: external (or upper) layer of columnar cells
2. Hypoblast (aka primitive endoderm): internal (or lower) layer of cuboidal cells
3. This two layered embryoblast is called the bilaminar embryonic disc or bilaminar blastoderm.
4. With this process the primitive dorsal-ventral axis of the embryo is defined.
a) 14 Day embryo: still has the form of a flat bilaminar embryonic disc.
(1) Hypoblastic cells in a localized area are now columnar and form a thickened circular area called the Prechordal Plate.
(a) Prechordal plate indicates the site of the mouth and is an important organizer of the head region.

III.Development of Amniotic Cavity

A. Day 8: when the amniotic cavity appears, as fluid beings to collect between cells of the epiblast and overlying trophoblast.
B. A layer of epiblast cells expands toward the embryonic pole and differentiates into a thin membrane separating the new cavity from the
cytotrophoblast.
1. This membrane is the lining of the amnion
C. The amniotic cavity expands steadily.
D. Week 8: amnion encloses the entire embryo

IV. Development of the Yolk Sac

A. Proliferation of hypoblast cells and 2 successive waves of cell migration form the yolk sac membranes
1. These extend from the hypoblast into the blastocyst cavity
2. Day 8: First wave of migration begins and forms the primary yolk sac (aka the exocoelomic membrane or Heuser’s
membrane)
a) Simultaneously, the extraembryonic mesoderm forms, filling the remainder of the blastocyst cavity with loosely arranged
cells.
3. Day 12: the primary yolk sac is displaced by the 2nd wave of migrating hypoblast cells, forming the secondary yolk sac.
a) The extraembryonic coelom (chorionic cavity) forms a new space by splitting the extraembryonic mesoderm in to 2 layers.
(1) It separates the embryo with its attached amnion and yolk sac from the outer wall of the blastocyst, now called the Chorion.
4. Day 13: The connecting stalk (a thick stalk of extraembryonic mesoderm) suspends the embryonic disc with its dorsal amnion and
ventral yolk sac into the chorionic cavity.
B. The yolk sac is an extraembryonic membrane that contains a cavity.
1. Formation and splitting of the extraembryonic mesoderm forms the Definitive yolk sac: a two layered structure consisting of
hypoblast-derived endoderm on the inside and mesoderm on the outside.
a) Extraembryonic mesoderm: forming the outer layer of the yolk sac is a major site of hematopoiesis.
(1) Hematopoiesis: the production of blood cells and platelets, which occurs in the bone marrow.
C. Primordial germ cells can be first identified in humans in the wall of the yolk sac
D. After Week 4: yolk sac is rapidly overgrown by the developing embryonic disc.
E. Yolk Sac normally disappears after birth, but on rare occasions it persists in the form of a digestive tract anomaly called Meckel’s
diverticulum.

V. Development of the Chorion

A. The extraembryonic coelom splits the extraembryonic mesoderm into 2 layers:
1. Extraembryonic Somatic Mesoderm: lining the trophoblast and covering the amnion
a) The extramebryonic somatic mesoderm and the two layers of the trophoblast (cytotrophoblast and syncytiotrophoblast) form the
chorion.
(1) Chorion: forms the wall of the chorionic sac, within which the embryo, amniotic sac, and umbilical vesicle (yolk sac) are
suspended by the connecting stalk.
2. Extraembryonic Splanchnic Mesoderm: surrounding the umbilical vesicle.
B. The extraembryonic coelom is now called the Chorionic Cavity.
 Early Human Development - Block II

VI. Uteroplacental Circulation

A. System by which maternal and fetal blood flowing through the placenta come into close proximity and exchange gases
and metabolites by diffusion.
B. Day 9: when this system begins to form as vacuoles (trophoblastic lacunae) open within the syncytiotrophoblast.
1. Maternal capillaries near the syncytiotrophoblast then expand to form maternal sinusoids.
a) The sinusoids rapidly anastomose with the trophoblastic lacunae.
C. B/w Days 11 - 13: cytotrophoblast proliferates locally to form extensions that grow into the overlying syncytiotrophoblast.
1. The growth of these protrusions is induced by the underlying newly formed extraembryonic mesoderm.
2. These extensions of cytotrophoblast grow out into the blood-filled lacunae, carrying with them a covering of syncytiotrophoblast
(primary chorionic stem villi)
D. ~ Day 16: extraembryonic mesoderm associated with the cytotrophoblast penetrates the core of the primary stem villi, thus transforming
them into secondary chorionic stem villi.
E. ~ End of Week 3: villous mesoderm gives rise to blood vessels that connect with the vessels forming in the embryo proper, thus establishing
a working uteroplacental circulation.
1. Villi containing differentiated blood vessels are called tertiary chorionic stem villi.
F. Gases, nutrients, and wastes that diffuse between the maternal and fetal blood cross 4 tissue layers:
1. Endothelium of the villus capillaries
2. Loose connective tissue in the core of the villus (extraembryonic mesoderm)
3. Layer of the cytotrophoblast
4. Layer of the syncytiotrophoblast

VII. Complete Hydatiform Mole

A. ~ 0.1% to 0.5% of pregnancies, the fetus is entirely missing.
B. Complete Hydatiform Mole: the conceptus consists only of placental membranes
C. The placental villi of a complete mole are swollen and vesicular, resembling bunches of grapes
1. “hydatid” is from the Greek word hydatidos, meaning drop of water.
D. Complete moles often abort in early pregnancies
1. If not, they result in vaginal bleeding during the 6th to 16th weeks of pregnancy, often causing excessive nausea and vomiting.
a) Owing to elevated human chorionic gonadotrophin (hCG)
E. Cells of a complete mole have a diploid karyotype, but all chromosomes are derived from the father:
1. Dispermic Fertilization: 2 spermatozoa may fertilize an oocyte that lacks (or loses) its own nucleus
a) the two pronuclei then fuse to form a diploid nucleus.
2. Monospermic Fertilization: if a single spermatozoon inseminates an oocyte that lacks (or loses) its own nucleus
a) The resulting male pronucleus undergoes an initial mitosis without cytokinesis.
b) It produces a diploid nucleus, which duplicates its DNA once again before the first cleavage occurs.

VIII. Partial Hydatiform Mole

A. Some evidence of embryonic development is usually found in this.
B. Or rare occasions, an abnormal fetus is delivered.
C. The swollen villi are the hallmark of a complete mole are present only in patches.
D. The clinical symptoms are usually milder and slower to develop than in the case of compete moles.
1. Spontaneous abortion usually does not occur until the second trimester (4 - 6 months)
E. Karyotype analysis indicates that conceptuses of this type are usually triploid (69, XXX; 69, XXY; or 69, XYY), with two sets of
chromosomes from the father.

IX.Gestational Trophoblastic Tumors

A. Residual trophoblastic tissue remaining in the uterus after spontaneous abortion or surgical removal of a hydatiform
mole may give rise to a condition known as Persistent Trophoblastic Diseases, in which the mole remnant grows to form a
tumor.
1. Tumors arising from partial moles are usually benign.
2. When tumors arising from complete moles become malignant, they may grow as an invasive mole or as a metastatic
choriocarcinoma.
a) All cases of invasive moles are consequence of the hydatiform mole.
(1) Molar villi grow into the myometrium or its blood vessels.
(2) May grow into the broad ligament of the uterus
(3) Metastasizes to the vagina, vulva, lungs, and the brain.

X. Question: Which of the following statements regarding the syncytiotrophoblast is correct?


A. Surrounds the 8-day blastocyst D. Is derived from the cytotrophoblast
B. Has well-defined cell boundaries E. Is nonfunctional 

C. Shows little invasive activity
XI. Question: A blastocyst of ~ 2-weeks’ gestation was found in a gynecologic specimen sent to the laboratory for examination. A characteristic
feature of a blastocyst at about this age is which of the following?

A. Incomplete implantation of the endometrium
B. Presence of primary chorionic villi
C. Notochord is present
D. Intraembryonic coelom surrounds the yolk sac
E. Gastrulation is in progress. 

 Early Human Development - Block II
Third Week Of Development
I. Gastrulation
A. Week 3: Gastrulation is the beginning of morphogenesis (development of the body form)
B. All embryonic tissues, and axial orientation are established in embryos during this process.
C. Bilaminar disc is converted into a trilaminar embryonic disc called the gastrula.
D. Each of the 3 germ layers give rise to specific tissues and organs
1. Embryonic Ectoderm
a) Epidermis
b) CNS, PNS
c) Eyes, Internal ears
d) As neural crest cells
e) To many connective tissue of the head
2. Embryonic Endoderm
a) Epithelial linings of the respiratory and alimentary tracts
b) Glandular cells of associated organs such as the liver and pancreas
3. Embryonic Mesoderm
a) All skeletal muscles, blood cells, and lining of the blood vessels
b) All visceral smooth muscular coats
c) Serosal linings of all body cavities
d) Ducts and organs of the reproductive and excretory systems
e) Most of the cardiovascular system.

II. Formation of the Primitive Streak

A. Beginning of Week 3:
1. Formation of the primitive streak (a thickened linear band) on the surface of the epiblast.
a) First morphologic sign of gastrulation.
b) Appears caudally in the median plane of the dorsal aspect of the embryonic disc.
c) Results from the proliferation and movement of cells of the epiblast.
(1) Caudal end: the streak elongates by addition of cells.
(2) Cranial end: proliferates to form a primitive node.
2. Primitive groove develops in the primitive streak that is continuous with the primitive pit
a) These result from the ingression (inward movement) of epiblastic cells.
3. Cells leave the deep surface of the primitive streak and form mesenchyme (an embryonic connective tissue)
a) Some mesenchyme from mesoblast (undifferentiated mesoderm), which forms the embryonic mesoderm
b) Cells from the epiblast displace the hypoblast, forming embryonic endoderm in the roof of the umbilical vesicle
c) Cells remaining in the epiblast form the embryonic ectoderm.

III. Fate of the Primitive Streak

A. Early part of Week 4: actively forms mesoderm by the ingression of cells
1. Production of the mesoderm slows down after this.
B. Diminishes in relative size and becomes an insignificant structure in the sacrococcygeal region of the embryo
C. End of Week 4: undergoes degenerative changes and disappears.

IV. Formation of the Notochord

A. Mesenchymal cells migrate cranially from the primitive node and primitive pit forming a median cellular cord called the
notochord process
1. Notochord process grows cranially between the ectoderm and endoderm until it reaches the prechordal plate.
a) The lumen that is acquired by the notochord process called the notochord canal.
b) Prechordal plate is an important signaling center for controlling development of cranial strictures.
(1) It gives rise to the endoderm of the oropharyngeal membrane (future site of the oral cavity)
(2) Caudal to the primitive streak there is a cloacal membrane (future site of the anus)
2. Floor of the notochord process fuses with the embryonic endoderm and the fused layers degenerate.
a) Notochord canal comes into communication with the yolk sac and the floor of the notochord canal disappears.
b) Remains of the notochord process form the notochordal plate.
(1) In cranio-caudal sequence the notochord cells proliferate and the notochord plate infields to form the notochord.
(2) The neurenteric canal forms a transitory communication between the amniotic and yolk sac cavities.
(3) The notochord detaches from the endoderm and the neurenteric canal normally obliterates.
(a) The notochord extends from the oropharyngeal membrane to the primitive node.
i) Defines the primordial longitudinal axis of the embryo and gives it some rigidity.
ii) Provides signals necessary for the development of axial musculoskeletal structures and CNS
(1) Induces the overlying embryonic ectoderm to thicken and form the neural plate
iii) It degenerates as the bodies of the vertebrae form
iv) Small portions of it persist as the nucleus pulposus
B. Prechordal mesoderm is a mesenchymal population of neural crest origin, rostral to the notochord.
C. Middle of Week 3: intraembryonic mesoderm separates in to the ectoderm and endoderm everywhere EXCEPT:
1. At the oropharyngeal membrane
2. In the median plane cranial to the primitive node, where the notochord process is located
3. At the cloacal membrane.
 Early Human Development - Block II
V. Remnants of the Notochord
A. Can be a cause of benign and malignant tumors called chordomas
1. ~ 1/3 of chordomas occur at the base of the cranium and extend to the nasopharynx
2. Chordomas grow slowly and malignant forms infiltrate bone.

VI. Allantois
A. ~Day 16 when it appears as a small diverticulum from the caudal wall of the yolk sac
B. Extends into the connecting stalk
C. The allantoic mesoderm expands beneath the chorion and forms blood vessels that will serve the placenta
D. The proximal part of the original diverticulum persists through much of development as a stalked called the Urachus.
E. It is represented in adults by the median umbilical ligament
F. The blood vessels of the allantoic stalk become the umbilical arteries.

VII. Establishment of the Body Axes

A. Takes place before and during the period of gastrulation.
B. The A-P axis is signaled by cells at the cranial margin of the embryonic disc (Anterior Visceral Endoderm - AVE).
1. AVE expresses genes essential for head formation
a) Transcription factors OTX2, LIM1, HESX1
b) Secreted Factors Cerberus and Lefty
2. These factors inhibit Nodal activity in the cranial end of the embryo
a) The primitive streak itself is initiated and maintained by expression of Nodal (TGF-b family)
b) Nodal unregulated genes responsible for formation of dorsal and ventral mesoderm and head and tail structures
c) BMP4 is secreted thought the embryonic disc
d) BMP4 + FGF will centralize the mesoderm (to contribute to kidneys and body wall mesoderm)
e) Chordin: activated by the transcription factor Goosecoid
(1) Noggin and follistatin antagonize the activity of BMP4.
(a) As a result cranial mesoderm is dorsalized into notochord, somites, and somitomeres.
3. Goosecoid over- or under-expression
a) In a laboratory animal results in severe malformations of the head region, including duplications, similar to some types of
conjoined twins.
4. HNF-3b maintains the node and induces regional specificity in the forebrain and midbrain areas
a) Absence of HNF-3b: embryos fail to gastrulate properly and lack forebrain and midbrain structures.
5. The Bracyury (T) gene expressed in the node, notochord precursor cells, and notochord.
a) Absence of the product of this gene results in shortening of the embryonic axis - caudal dysgenesis
b) The degree of shortening depends on the time at which the protein becomes deficient.
C. Caudal dysplasia, also called caudal regression syndrome, caudal agenesis, or sacral agenesis is characterized by varying degrees of:
1. Flexion, inversion, and lateral rotation of the lower extremities
2. Anomalies of lumbar and sacral vertebrae
3. Imperforate anus
4. Agenesis of the kidneys and urinary tract
5. Agenesis of the internal genital organs except for the gonads.
D. In extreme cases the lower limb bud fuse during early development, resulting in a “mermaid-like” habits called sirenomelia.
1. VATER association:
a) Vertebral defects
b) Anal atresia
c) Tracheal-Esophageal fistula
d) Renal defects and Radial forearm anomalies
2. VACTERL association:
a) also includes Cardiovascular anomalies with Renal and Limb defects
E. Remnants of the primitive streak may persist and give rise to a sacrococcygeal teratoma
1. These tumors contain tissues derived from all three germ layers in incomplete stages of differentiation
2. Sacrococcygeal teratomas are the most common tumor in newborns and have an incidence of approximately one in 35,000
a) Most affectegd infants (80%) are female.
F. Laterality (left-right-sidedness) also is established early in development
1. Alterations in 5HT signaling result in situs inversus, dextrocardia, and a variety of heart defects.
2. Genes regulating right-sided development are not as well defined.

VIII. Laterality Defects

A. Normal L-R positioning of the organs is called situs solitus.
B. Their complete reversal is called situs inversus.
C. When one or more organs are abnormally positioned the condition is called situs ambiguous or heterotaxy
D. Patients with the right-sided bilaterally have asplenia or hypo plastic spleen.
E. Those with the left-sided bilaterally have polysplenia

IX. Fate Map of Epiblast Cells

A. Experiments have shown that most cells within the epiblast and primitive streak are pluripotent and that their fates are
specified by cell-cell interactions that occur during their migration, or shortly after they arrive at their final destination.
 Early Human Development - Block II
X. Alcohol Effects During Gastrulation
A. High doses of the alcohol at this stage destroy cells in the anterior midline of the germ disc
1. This results in holoprocencephaly
a) Forebrain is small, lateral ventricles merge, hypotelorism.

XI. Neurulation
A. The processes involved in the formation of the neural plate and neural folds and closure of the folds to form the neural tube constitute.
B. End of 4th Week: Neurulation is completed with the closure of the caudal neuropore.
1. Molecular Regulation:
a) FGF signaling
b) BMP4 inhibited
c) Secretion of the noggin, chordin, follistatin, inactivates BMP
2. Induction of the caudal neural plate structures (hindbrain and spinal cord) depends on WNT3a and FGF proteins.
C. End of the 3rd Week: the lateral edges of the neural plate become elevated to form neural folds, and the depressed mid-region forms the
neural groove.
1. Gradually, the neural folds approach each other in the midline, where they fuse
a) Fusion begins in the cervical region (5th somite) and proceeds cranially and caudally, as a result, the neural tube is formed.
(1) The cephalic and caudal ends of the neural tube communicate with the amniotic cavity by way of the anterior (cranial) and
posterior (caudal) neuropores, respectively.
(a) ~Day 25 (18 to 20 somite stage): closure of the cranial neuropore
(b) Day 28 (25 somite stage): closure of posterior neuropore
i) Neurulation is then complete, and the CNS is represented by a closed tubular structure with a narrow caudal
portion, the spinal cord, and a cephalic portion characterized by a number of dilations, the brain vesicles.

XII. Neural Crest Cells

A. Cells at the lateral border or crest of the neuroectoderm dissociate form their neighbors.
1. This cell population, the neural crest, will undergo an epithelial-to-mesenchymal transition as it leaves the neuroectoderm by active
migration and displacement to enter the underlying mesoderm.
B. Crest cells from the trunk region leave the neuroectoderm after closure of the neural tube and migrate along one of two pathways:
1. A dorsal pathway through the dermis (to form melanocytes in the skin and hair follicles)
2. A ventral pathway through the anterior half of each somite to become sensory ganglia, sympathetic and enteric neurons, Schwann’s
cells, and cells of the adrenal medulla.

XIII. Secondary Neurulation

A. Secondary neurulation involves the condensation of central tail bud cells into a solid mass called the medullary cord
1. The medullary cord undergoes cavitation to form a lumen
a) It quickly merges with neural canal of the more cranial neural tube.
2. Neural crest cells migrate to form the caudal spinal ganglia.
3. Lateral tail bud cells undergo segmentation to form the caudal somites
4. The caudal end of the notochord grows into the sacral, coccygeal, and tail regions
5. ~Week 8: secondary neurulation is completed

XIV. Derivatives of the Ectoderm

A. The CNS
B. The PNS
C. Sensory epithelium of the ear, nose, and eye
D. The epidermis, including the hair and nails
E. It gives rise to:
1. Subcutaneous glands
2. Mammary glands
3. Pituitary glan
4. Enamel of the teeth

XV. Neural Tube Defects

A. Result from the failure of the neural tube closure
B. Anencephaly
C. Spina bifida
D. Prevention: 400 mg of folic acid daily

XVI. Question: Prospective fate maps are used to determine which of the following?
A. Where stem cells are localized
B. Where differentiated cells are localized
C. Where the cells arise in the embryo that give rise to its different parts
D. Where apoptosis occurs
E. Where different genes are expressed in the embryo
XVII. Question: The notochord process lengthens by migration of cells from which of the following?

A. Notochord C. Notochordal Plate E. Neural Plate
B. Primitive Streak D. Primitive Node