MS-1 FUND 1: 11:00-12:00
Friday, September 12, 2014
Dr. Chang Embryology
Early Embryogenesis
Transcriber: Wade Edwards
Editor: Leslie Williams
Page 1 of 4
Abbreviations: EM= Electron Microscopy, GI = Gastrointestinal, FGF = Fibroblast Growth Factor, TGFB = Transforming Growth Factor Beta, BMP =
Bone Morphogenetic Protein, NTD = Neural Tube Defect, HOX = Homeobox Transcription Factors, SHH = Sonic Hedgehog, PNS= Peripheral Nervous
System
Introductory Comments: This is the second hour of Dr. Chang’s Early Embryogenesis lecture. This transcript was taken from the
2013 echo as this was a self-study lecture. At the start of this lecture, Dr. Cotlin stated that Dr. Chang goes into more detail than our
textbooks because the textbooks do not provide in depth information, but that we will be tested on information in the PowerPoint and
the stuff Dr. Chang speaks about.
I.
II.
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The Third and Fourth Week of Human Development (Slide 44) 8:32
a. Gastrulation and Neurulation are two important events that both occur during the third and fourth week of
development.
b. Neurulation occurs at the end of the third week.
Gastrulation (Slide 45) 9:31
Gastrulation is the development of three distinct germ layers (endoderm, mesoderm, ectoderm) from the epiblast.
The epiblast is a single layered disc that will differentiate during gastrulation to form three layers.
Ectoderm is the outside layer, mesoderm is the middle, and endoderm is the innermost layer.
Quote by Lewis Wolpert: “It is not birth, marriage, or death, but gastrulation that is truly the most important time in your
life.”
a. Without gastrulation, no birth will occur (spontaneous abortion).
How is gastrulation accomplished? (Slide 46) 11:03
a. Gastrulation occurs via coordinated cell movements.
b. During gastrulation, there is a massive amount of cell rearrangement.
i. The epiblast cells move toward the center, making the density of the cells in the center higher than on the
outside. This leads to a dark colored structure named the primitive streak.
ii. As the cells move toward the center, they dive down.
iii. Some of these cells will migrate into the underlying hypoblast layer and displace it gradually to form the
endoderm.
iv. Some of them will migrate between the epiblast and endoderm to form the embryonic mesoderm.
v. Cells that do not transverse through the primitive streak give rise to the ectoderm.
vi. Cells also move to the anterior portion of the primitive streak to form the Hensen’s Node, which is a thicker
region and is important in neural development.
Generation of Three Germ Layers (Slide 47) 14:09
a. Scanning EM on slide shows the epiblast.
b. As the cells move into the primitive streak, they will come down.
c. One group replaces hypoblast to become the embryonic endoderm. Cells that stay in between become mesoderm.
Cells that remain on top become ectoderm.
Types of Cell Movements (Slides 48-49) 14:34
a. Cell Ingression - Cells moving through primitive streak do so as individual cells. They then detach from the epiblast
cells that have remained in the epiblast.
b. Cell Migration - After they move away from the epiblast, these cells will migrate out into different layers between
the hypoblast and epiblast.
c. Intercalation– This cell movement is when two layers of cells move together and squeeze in between each other to
ultimately form a single layer.
d. Convergent Extension - Some cells will also mix between each other to make their body axis longer via
intercalation. Convergent extension allows the cells to take an elongated shape, rather than rounded and is how body
elongates itself.
e. Epiboly – The ectodermal cells can move around the embryo and wrap it in. Epiboly involves both cell division and
cell shape change
f. Slide 49 shows an example of these types of cell movements and others such as invagination. The end result of
these cell movements is that the embryo becomes elongated and narrower.
Cell Movements and Cell Fates (Slides 50-51) 18:37
a. As cells are moving down primitive streak they migrate out in different directions.
i. Some cells also stay closer to the primitive streak while others move further away.
ii. The distance that they move away from the primitive streak will determine what they eventually
differentiate into.
1. Anterior migration of mesodermal cells contributes to head mesoderm, head endoderm, and heart
mesoderm
2. The cells that stay closest to the primitive streak will form the notochord, a rod like structure in the
midline which will later contribute to vertebral column in adult. These cells are called axial cells.
MS-1 FUND 1: 11:00-12:00
Friday, September 12, 2014
Dr. Chang Embryology
Early Embryogenesis
Transcriber: Wade Edwards
Editor: Leslie Williams
Page 2 of 4
Abbreviations: EM= Electron Microscopy, GI = Gastrointestinal, FGF = Fibroblast Growth Factor, TGFB = Transforming Growth Factor Beta, BMP =
Bone Morphogenetic Protein, NTD = Neural Tube Defect, HOX = Homeobox Transcription Factors, SHH = Sonic Hedgehog, PNS= Peripheral Nervous
System
3.
VII.
VIII.
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XI.
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Lateral to the axial region, are the paraxial cells which will form the somites. Somites are a repetitive
block structure which gives rise to skeletal muscle, and dermis.
4. Lateral to the paraxial region is the intermediate mesoderm. Intermediate mesoderm will form the
gonads and kidneys.
5. The most lateral region is called the lateral plate mesoderm, which forms the lateral and ventral wall of
the body, walls of the digestive system, and arms and legs.
Fates of Cells from the three germ layers (Slide52) 21:42
a. Endoderm – Forms the lining of the GI tract, lining of lungs. The liver, and pancreas also come from endoderm
b. Mesoderm- Forms the bulk of bones and muscle. In addition, forms the heart, kidney, and gonads.
c. Ectoderm – Forms the skin, the Nervous System, and sensory organs.
Mesodermal and Endodermal Cell Fate Specification (Slides 53-55) 23:21
a. The fates of different germ layers are under control of different growth factors.
i. Transforming Growth Factor Beta (TGFB) – Induces both mesoderm and endoderm. At high doses, it
specifies endoderm specification, and at intermediate doses it specifies mesoderm differentiation. When no
TGFB exists, ectoderm is specified. TGFB is a large family of ligands, the most important one is called the
Nodal one.
ii. WNT and Fibroblast Growth Factor (FGF) – two others that are involved in mesoderm/endoderm
specification
iii. TGFB Pathway– The ligand binds to the receptor of the cell surface which activates the SNAP protein, a
signal transducer, and then they collaborate to contribute initiate transcription in endodermal and
mesodermal cells.
iv. Canonical WNT Pathway– the WNT ligand binds to a cell surface receptor, which activates the BetaCatenin protein. In the absence of WNT ligand, Beta-Catenin is degraded in the cytosol. When WNT
binds, Beta-Catenin is stabilized and can be translocated in cytosol to initiate transcription. <ARS 26:1526.50>
Formation of the Nervous System: Neurulation – (Slide 56-57) 26:51
a. Neurulation is the formation of the Nervous System.
b. Neural tissue induction occurs soon after gastrulation at the end of the third week.
c. Neurulation is specifically the process where the neural plate folds into a neural tube to form the spinal cord and
central nervous system.
i. The neural plate is initially a flat sheet, and then folds inward to make the neural tube.
1. Neural Crest Cells are a special type of cell that come together from ends of neural plate. They actively
migrate to form the Peripheral Nervous System.
Signals involved in Neural Induction (Slide 58) 29:46
a. Bone Morphogenetic Protein (BMP)
i. BMP belongs to TGFB family of growth factors.
ii. BMP must be inhibited for neural cells to differentiate.
iii. BMP levels affect ectodermal differentiation.
1. High BMPepidermal
2. Low BMPneuronal
3. Intermediate BMP neural crest
iv. Neural tissue is induced by the notochord and somites, which secrete BMP inhibitors.
Closure of the Neuropores (Slide 59) 31:59
a. The neural tube closure begins in the middle of the embryo and spreads out both anteriorly and posteriorly.
i. These closures are called the neuropores and help seal off the neural tissue from the outside.
ii. Neural tube closure defects are a common birth defect; these are termed Neural Tube Defects (NTDs).
1. If the anterior neuropore fails to close, it is called anencephaly and the embryo is stillborn.
2. The posterior neuropore closure failure is Spina Bifida. Non-Canonical WNT pathway is a
controller of this process
Apical Constriction (Slide 60) 34:33
a. The neural tube uses hinge points to help form the neural pore closure.
b. Convergent extension occurs at the hinge points that allows the tissue to come together.
Neural Tube Closure Defects (Slide 61) 35:18
a. Occur in about 1/1000 live births.
b. Craniorachischisis is another NTD that occurs when multiple parts of the neuropore do not close
i. Lethal NTD
Non-Canonical WNT Pathway (Slide 62) 36:08
MS-1 FUND 1: 11:00-12:00
Friday, September 12, 2014
Dr. Chang Embryology
Early Embryogenesis
Transcriber: Wade Edwards
Editor: Leslie Williams
Page 3 of 4
Abbreviations: EM= Electron Microscopy, GI = Gastrointestinal, FGF = Fibroblast Growth Factor, TGFB = Transforming Growth Factor Beta, BMP =
Bone Morphogenetic Protein, NTD = Neural Tube Defect, HOX = Homeobox Transcription Factors, SHH = Sonic Hedgehog, PNS= Peripheral Nervous
System
XV.
XVI.
XVII.
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XXI.
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a. Non Canonical WNT pathways do not go through Beta Catenin protein like Canonical pathways do.
b. It uses other downstream effectors that regulate cytoskeleton and cell shape and polarity.
Differentiation of Neural Tube (Slide 63-66) 36:35
a. After the neural tube closes, it is not even in all spots. There is a cranial-caudal difference.
b. This difference is controlled by growth factor gradients and HOX transcription factors.
c. During this patterning of different portions of the neural tube, there is a high gradient of WNT signals at the caudal
end and low at the cranial end.
d. At the cranial end, they are actually inhibitors of the WNT signal pathway as well as FGF.
e. When you have a low signal, brain tissue is formed, and when high signal is present, spinal cord is formed.
f. HOX transcription factors are important in interpreting growth factor signals downstream and turning this into shape
change in the embryo.
Dorsal Ventral Patterning (Slide 67-69) 39:25
a. In addition to cranial/caudal patterning, there is also dorsal and ventral patterning.
i. Dorsal side of the neural tube has sensory neurons, ventral side has motor neurons with interneurons
connecting the two.
ii. Dorsal patterning is controlled by TGFB that specifies the sensory neurons in the dorsal neural tube to
differentiate.
iii. Sonic Hedgehog (SHH), is another growth factor that controls specification of ventral neuron in the
neural tube. SHH is secreted from the notochord.
iv. These growth factors form gradients, as some are in high concentrations and some are in low
concentrations. This all forms a sort of code that will tell the cells when and how to differentiate
depending on what type of growth factor is released at what time.
Neural Crest Cells – The fourth germ layer (Slide 70) 41:34
a. Neural Crest cells migrate after the neural tube folds.
b. Neural Crest cells give rise to the PNS, as well as glial cells in the PNS.
i. These cells can migrate very long distances in the body.
ii. They also form bone and muscle cells in the face, secretory cells in adrenal gland.
c. Since Neural Crest Cells give rise to both ectoderm like structures and mesoderm like structures, it is sometimes
called the 4th germ layer.
Derivatives of Neural Crest Cells (Slide 71-72) 43:04
a. Cranial Neural Crest Cells – Give rise to the bones and muscle and cartilage of the face as well as the bones of the
middle ear.
b. Cardiac Neural Crest Region – Forms the septum between the aorta and pulmonary arteries and also forms the walls
of the arteries
c. Caudal Neural Crest Region (Trunk Region) – Gives rise to melanocytes (pigment cells) as well as parasympathetic
ganglia that innervate the GI tract.
Neural Crest Induction (Slide 73) 45:05
a. Interaction between neural plate and ectoderm is important for specification and migration of neural crest cells.
b. The underlying mesoderm also secretes induction factors.
i. Once again, BMP, WNT, and FGF signals are involved in the induction process.
ii. Intermediate levels of BMP are important for Neural Crest Induction. FGF signals come from mesoderm.
Neural Crest Induction: Gene Regulatory Network (Slide 74) 46:07
a. Downstream of the signals are many transcription factors which are turned on by the growth factors
Migration of Trunk Neural Crest (Slide 75) 46:22
a. Can take two different routes:
i. Dorsolateral route: Goes under the surface of the ectoderm; found in melanocytes
ii. Ventrolateral route: Can migrate down the neural tube before branching out. Found in anterior sclerotome,
dorsal root ganglia, sympathetica ganglia
iii. Ephrin and Semaphorin both serve as repellent signals for crest cell migration.
Differentiation: Pluripotency (Slide 76-77) 47:17
a. Neural cells at the same region can give rise to different derivatives, suggesting that the fates of neural crest cells are
not pre-determined before they leave the neural tube.
b. Neural Crest cells are said to be pluripotent since they can become multiple cell types. They migrate until they
receive a signal telling them to differentiate.
i. Exposure to FGF neuron
ii. Exposure to glucocorticoidschromaffin
Cranial Neural Crest Malformations (Slide 78) 48:29
MS-1 FUND 1: 11:00-12:00
Friday, September 12, 2014
Dr. Chang Embryology
Early Embryogenesis
Transcriber: Wade Edwards
Editor: Leslie Williams
Page 4 of 4
Abbreviations: EM= Electron Microscopy, GI = Gastrointestinal, FGF = Fibroblast Growth Factor, TGFB = Transforming Growth Factor Beta, BMP =
Bone Morphogenetic Protein, NTD = Neural Tube Defect, HOX = Homeobox Transcription Factors, SHH = Sonic Hedgehog, PNS= Peripheral Nervous
System
Cleft lip – lip tissue doesn’t come together correctly at the midline. Surgery will correct this issue.
Waardenburg Syndrome – Cochlear deafness, multicolored or hyper pigmented irises, a broad nasal bridge and a
white forelock.
c.
DiGeorge Syndrome Cardiac defects, abnormal face, thymic hypoplasia, cleft palate, hypocalcemia, with deletion in
chromosome 22q11.2 (SN: She did not mention the last two types of cranial malformation, but they were on her slide.)
Cardiac Neural Crest Malformations & Trunk Neural Crest Malformations (Slide 79) 49:15
a. Cardiac: causes Persistent truncus arteriosus- failure of the aorta and pulmonary artery to separate
b. Trunk: causes Hirschprungs Disease
Early Human Embryonic Development (Slide 80) 50:04
a. This is an overview slide showing each phase of embryonic development happens.
i. Fertilization, cleavage, and blastocyst formation occur during week 1.
ii. Implantation occurs during Week 2.
iii. Gastrulation in Week 3.
iv. Neurulation is Week 4.
v. After this, the embryo undergoes organogenesis to form a functioning baby.
Critical Periods in Human Development (Slide 81) 51:05
a. This slide depicts critical periods during embryo development.
b. If defects occur during early stages, spontaneous abortion will occur (prior to gastrulation).
c. Embryogenesis is susceptible to many environmental factors.
d. The first 4 weeks are very important for baby to take shape.
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XXVI.
No Student Questions.
<End of Lecture 51:44>