Gastrulation and Neurulation

Both gastrulation and neurulation are critical events that occur during the 3rd week of embryonic development. Gastrulation is the process by which the bilaminar disc differentiates into a trilaminar disc, made up of the 3 primary germ layers: the ectoderm, mesoderm, and endoderm. During this process, a structure called the notochord is formed in the midline in the mesodermal layer; the notochord is critical in inducing neurulation. Neurulation is the process by which some of the ectoderm in the trilaminar embryo develops into the neural tube and neural crest cells, which will go on to form all of the neural tissue in the body. This process is completed by the end of the 3rd week.

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Review of Early Development

Morula, blastocyst, and bilaminar disc

  • Zygote: diploid cell resulting from the fusion of 2 haploid gametes
  • Blastomeres: individual cells at the 2-, 4-, and 8-cell stages
  • Morula: “ball of cells” starting at the 16-cell stage
  • Blastocyst:
    • Morula develops a cavity called a blastocele.
    • “Positional signals” (i.e., signals released from different cells based on their position in the blastocyst) trigger cells to differentiate into: 
      • Outer cell mass: outer shell of cells
      • Inner cell mass: a clump of cells inside the shell next to the blastocele
  • Zona pellucida: 
    • A layer of extracellular matrix surrounding embryo through the blastocyst stage
    • Prevents embryo from implanting in the fallopian tubes (where fertilization typically occurs)
  • Outer cell mass → trophoblast (cytotrophoblast and syncytiotrophoblast) → placenta and membranes
  • Inner cell mass → embryoblast → bilaminar disc:
    • Epiblast: dorsal layer
    • Hypoblast: ventral layer
  • Amniotic sac: a cavity of fluid that develops “above” the epiblast (between epiblast and cytotrophoblast)
  • Primary yolk sac: a cavity that forms “below” the hypoblast (between hypoblast and cytotrophoblast)

Implantation

  • Occurs around days 7–9 after fertilization
  • Cytotrophoblast: outer layer of cells of blastocyst
  • Syncytiotrophoblast: 
    • Trophoblast cells in contact with uterine wall that have lost their outer membranes → simply “nuclei” floating in cytoplasm
    • As the cell membranes rupture, hydrolytic enzymes are released, allowing the embryo to “eat its way” into the uterine wall.
  • A layer of endometrium (decidua functionalis) covers the invading blastocyst = implantation

Gastrulation

Overview of gastrulation

  • Gastrulation is the process by which the bilaminar disc develops into the trilaminar disc.
  • Establishes all 3 primary germ layers:
    • Ectoderm (dorsal)
    • Mesoderm (middle)
    • Endoderm (ventral)
  • Occurs during the 3rd week (memory trick: 3rd week = 3 layers)
  • Process begins with formation of the primitive streak on the surface of the epiblast.
Process of gastrulation

Process of gastrulation:
Cells from the epiblast migrate down through the primitive streak and displace most of the hypoblast cells, becoming the endoderm. Cells that remain in the middle become the mesoderm. Cells that remain in the epiblast layer become the ectoderm.

Image: “Germ Layers” by Phil Schatz. License: CC BY 4.0

Primitive streak and the primitive groove

  • Primitive streak: an area in the midline of the epiblast layer begins to thicken: 
    • Forms around day 16 of development 
    • Starts at the caudal end → extends < halfway down the embryo toward the cranial end
    • Establishes the main body axis:
      • Cranial and caudal ends
      • Left and right
    • Primitive node: more prominent area at cranial end of primitive streak
  • Primitive groove: appears as small depression in primitive streak
  • Primitive pit: depression within primitive node that will develop into notochord
  • Fibroblast growth factor 8 (FGF8):
    • Secreted by cells in the primitive streak/groove
    • Inhibits the production of adhesion molecules holding the epiblast cells together
    • Without adhesion proteins → epiblast cells can migrate
  • Prechordal plate: a compact area at the cranial end of the embryo
Beginning of gastrulation

Beginning of gastrulation:
The primitive streak and primitive groove form in the bilaminar disc.

Image by Lecturio.

Epiblast migration

  • Epiblast cells migrate toward the primitive streak → down the primitive groove
  • These cells elongate downward, creating space between the epiblast and the hypoblast 
  • These cells detach from the epiblast and slip beneath it (invagination) 
  • Detached epiblast cells replace the hypoblast cells → become the endoderm
  • Epiblast cells continue to migrate → detach → invaginate → fill the space between the epiblast and endoderm → become the mesoderm
  • Cells that remain in the epiblast layer → become the ectoderm
  • Migration is complete early in the 4th week
Migration of epiblast cells

Migration of epiblast cells through the primitive groove:
These epiblast cells displace the hypoblast to become the endoderm and create a middle layer known as mesoderm. Epiblast cells that remain on the dorsal surface differentiate into ectoderm.

Image by Lecturio.

The trilaminar disc

  • Ectoderm: cells remaining in the epiblast layer (continuous with the amnion)
  • Mesoderm: cells that invaginated beneath epiblast (middle layer)
    • Paraxial mesoderm
    • Intermediate mesoderm
    • Lateral plate mesoderm (LPM): 
      • Somatic layer
      • Splanchnic layer
    • Extraembryonic mesoderm:
      • Surrounds the amniotic cavity → continuous with somatic LPM
      • Surrounds the yolk sac → continuous with splanchnic LPM
  • Endoderm: cells that invaginated beneath the epiblast and replaced the hypoblast: 
    • Embryonic endoderm (usually just called endoderm) → becomes primitive gut tube
    • Extraembryonic endoderm → lines secondary yolk sac
  • Secondary yolk sac: cavity between embryonic and extraembryonic endoderm
Layers of the trilaminar disc

Layers of the trilaminar disc

Image by Lecturio.

Formation of the chorionic cavity

  • Chorionic cavity:
    • Develops within the extraembryonic mesoderm
    • Surrounds the 1st-degree yolk sac, embryoblast, and amniotic cavity
  • Body stalk: anchors the embryo to the uterine wall → becomes the umbilical cord
Chorionic cavity

Formation of the chorionic cavity

Image by Lecturio.

Formation of the notochord

  • Notochord: chord-like structure that runs along the embryo
  • Appears in 3rd week of development during gastrulation
  • Process of notochord formation:
    • Ectodermal cells invaginate in primitive pit → mesodermal cells
    • Mesodermal cells move cranially in midline until they reach the prechordal plate
    • Mesodermal cells create a tube-like structure
  • Function: induces overlying ectoderm to differentiate into the neural plate (start of neurulation)
  • Persists postnatally as the nucleus pulposus (soft gelatinous central portion of the intervertebral disk)
Formation of the notochord during gastrulation

Formation of the notochord during gastrulation.

Image by Lecturio.

Neurulation

Neurulation is the process by which ectoderm in the trilaminar embryo develops into the neural tube. Beginning in the 3rd week, a group of ectodermal cells progresses through the following structures:

  • Notochord: induces differentiation of ectodermal cells above it to form neural plate
  • Neural plate: thickening of ectoderm along the midline
  • Neural groove: a depression forms in the center of neural plate
  • Neural folds: 
    • Consists of cells forming lateral walls around neural groove, which elevate slightly above the rest of the ectoderm
    • The “uppermost” cells on the neural folds differentiate into neural crest cells, which form a number of different peripheral nervous structures.
  • Neural tube: 
    • The neural folds circle upward and meet in the midline, forming a tube
    • This tube is pulled below the outer layer of ectoderm → now known as the neural tube
    • Neural crest cells separate and are located between the neural tube and the ectoderm.
    • Cranial portion of neural tube: enlarges to become the brain
    • Caudal portion of neural tube: remains tubular, becomes the spinal cord

Development requires folate; folate deficiency → neural tube defects

The process of neurulation

The process of neurulation:
Neural crest cells (green) are derived from the neural plate (gray), which folds upwards and inwards towards the midline to create the neural tube.

Image by Lecturio.

Derivatives of the Trilaminar Embryo

Ectoderm derivatives

  • Surface ectoderm (outer layer of ectoderm remaining after neurulation):
    • Skin, hair, and nails
    • Adenohypophysis (anterior pituitary)
    • Lens of the eye
    • Epithelial linings in the:
      • Oral cavity 
      • Anal canal below pectinate line
      • External auditory canal
    • Glands:
      • Salivary 
      • Sweat
      • Mammary
  • Neural tube (CNS):
    • Brain
    • Spinal cord
    • Retina
  • Neural crest cells (PNS):
    • Autonomic nervous system
    • Enteric nervous system (in the GI tract)
    • Cranial nerves
    • Schwann cells
    • Adrenal medulla
    • Melanocytes
    • Aorticopulmonary septum

Mesoderm derivatives

  • Muscle (all 3 types):
    • All skeletal muscles
    • Cardiac: heart
    • All smooth muscle (e.g., in bowel wall, bronchial walls, uterus, vessel walls)
  • Bone, cartilage, and connective tissue
  • Blood and lymphatic vessels
  • Blood
  • Peritoneum, mesenteries, and ligaments in the abdominal cavity
  • Organs:
    • Kidneys and ureters
    • Adrenal cortex
    • Spleen
    • Gonads (testes and ovaries)
    • Upper vagina

Endoderm derivatives

  • Endothelial lining of the respiratory tree
  • Endothelial lining and mucosal glands of the entire GI tract down to the pectinate line in the anal canal (memory trick: endoderm is the enteral layer)
  • Liver
  • Gallbladder and biliary tree
  • Pancreas
  • Bladder and urethra
  • Lower vagina
  • Thymus

Clinical Relevance

Abnormal gastrulation

Spontaneous abortion (miscarriage): abnormalities of gastrulation typically result in multiple congenital anomalies. These embryos are typically incompatible with life, and the result is a spontaneous loss of the pregnancy, usually in the 1st trimester. 

Neural tube defects

Neural tube defects (NTDs): caused by the failure of the neural tube to close properly during embryologic development, potentially resulting in protrusion of neural tissue. Neural tube defects may involve the spinal cord and/or cranium and may be open (involving the meninges and/or neural tissue) or closed (involving the bony vertebral column). Prenatal diagnosis by ultrasonography and maternal α-fetoprotein level is common. Management of open NTDs is mainly surgical. 

  • Open NTDs of the spinal cord:
    • Meningocele: only meninges protrudes
    • Meningomyelocele: both meninges and spinal cord protrude (most common NTD)
  • Open NTDs of the cranium:
    • Cranial meningocele: only meninges protrude
    • Cranial encephalocele: both meninges and brain stem/cerebellum/cerebral cortex protrude 
    • Anencephaly: complete failure of cephalic neural tube to close, resulting in fully exposed fetal brain (not compatible with life)
  • Closed NTDs: midline defect of vertebral bodies without protrusion of meninges or neural tissue:
    • Spina bifida occulta: without a subcutaneous mass
    • Lipomeningocele or lipomyelomeningocele: with a subcutaneous mass

References

  1. Carlson, B.M. (Ed.). (2018). Human Embryology and Developmental Biology, 6th ed. Elsevier.
  2. Sadler, T. W. (2018). Langman’s Medical Embryology, 14th ed. Lippincott Williams & Wilkins.
  3. Muhr, J. (2021). Embryology, gastrulation. StatPearls. Retrieved October 29, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/22120/ 
  4. OpenStax College. (n.d.). Anatomy and physiology. OpenStax CNX. Retrieved October 29, 2021, from https://philschatz.com/anatomy-book/contents/m46319.html 

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