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 Fertilization To undergo fertilization, the sperm enters the uterus, travels towards the ampulla of the fallopian tube, and encounters the oocyte. The zona pellucida (the outer layer of the oocyte) deteriorates along with the zygote, which travels towards the uterus and eventually forms a blastocyst, allowing for implantation to occur. Fertilization and First Week typically occurs)
  • Outer cell mass → trophoblast (cytotrophoblast and syncytiotrophoblast) → placenta Placenta The placenta consists of a fetal side and a maternal side, and it provides a vascular communication between the mother and the fetus. This communication allows the mother to provide nutrients to the fetus and allows for removal of waste products from fetal blood. Placenta, Umbilical Cord, and Amniotic Cavity 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 Fertilization To undergo fertilization, the sperm enters the uterus, travels towards the ampulla of the fallopian tube, and encounters the oocyte. The zona pellucida (the outer layer of the oocyte) deteriorates along with the zygote, which travels towards the uterus and eventually forms a blastocyst, allowing for implantation to occur. Fertilization and First Week
  • 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 Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of 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 Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord

Development requires folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12; folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 deficiency → neural tube defects Neural tube defects Neural tube defects (NTDs) are the 2nd-most common type of congenital birth defects. Neural tube defects can range from asymptomatic (closed NTD) to very severe malformations of the spine or brain (open NTD). Neural tube defects are caused by the failure of the neural tube to close properly during the 3rd and 4th week of embryological development. 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 Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the 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 Autonomic nervous system The ANS is a component of the peripheral nervous system that uses both afferent (sensory) and efferent (effector) neurons, which control the functioning of the internal organs and involuntary processes via connections with the CNS. The ANS consists of the sympathetic and parasympathetic nervous systems. Autonomic Nervous System
    • Enteric nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System (in the GI tract)
    • Cranial nerves Cranial nerves There are 12 pairs of cranial nerves (CNs), which run from the brain to various parts of the head, neck, and trunk. The CNs can be sensory or motor or both. The CNs are named and numbered in Roman numerals according to their location, from the front to the back of the brain. Overview of the 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 Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones, cartilage Cartilage Cartilage is a type of connective tissue derived from embryonic mesenchyme that is responsible for structural support, resilience, and the smoothness of physical actions. Perichondrium (connective tissue membrane surrounding cartilage) compensates for the absence of vasculature in cartilage by providing nutrition and support. Cartilage, and connective tissue Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. Connective Tissue
  • Blood and lymphatic vessels
  • Blood
  • Peritoneum Peritoneum The peritoneum is a serous membrane lining the abdominopelvic cavity. This lining is formed by connective tissue and originates from the mesoderm. The membrane lines both the abdominal walls (as parietal peritoneum) and all of the visceral organs (as visceral peritoneum). Peritoneum and Retroperitoneum, mesenteries, and ligaments in the abdominal cavity
  • Organs:
    • Kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys and ureters
    • Adrenal cortex
    • Spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen
    • Gonads (testes and ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries)
    • Upper vagina Vagina The vagina is the female genital canal, extending from the vulva externally to the cervix uteri internally. The structures have sexual, reproductive, and urinary functions and a rich blood supply, mainly arising from the internal iliac artery. Vagina, Vulva, and Pelvic Floor

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 Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver
  • Gallbladder Gallbladder The gallbladder is a pear-shaped sac, located directly beneath the liver, that sits on top of the superior part of the duodenum. The primary functions of the gallbladder include concentrating and storing up to 50 mL of bile. Gallbladder and Biliary Tract and biliary tree
  • Pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas
  • Bladder and urethra
  • Lower vagina Vagina The vagina is the female genital canal, extending from the vulva externally to the cervix uteri internally. The structures have sexual, reproductive, and urinary functions and a rich blood supply, mainly arising from the internal iliac artery. Vagina, Vulva, and Pelvic Floor
  • Thymus

Clinical Relevance

Abnormal gastrulation

Spontaneous abortion Spontaneous abortion Spontaneous abortion, also known as miscarriage, is the loss of a pregnancy before 20 weeks' gestation. However, the layperson use of the term "abortion" is often intended to refer to induced termination of a pregnancy, whereas "miscarriage" is preferred for spontaneous loss. 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 Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care, 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 Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord and/or cranium and may be open (involving the meninges Meninges The brain and the spinal cord are enveloped by 3 overlapping layers of connective tissue called the meninges. The layers are, from the most external layer to the most internal layer, the dura mater, arachnoid mater, and pia mater. Between these layers are 3 potential spaces called the epidural, subdural, and subarachnoid spaces. Meninges and/or neural tissue) or closed (involving the bony vertebral column Vertebral column The human spine, or vertebral column, is the most important anatomical and functional axis of the human body. It consists of 7 cervical vertebrae, 12 thoracic vertebrae, and 5 lumbar vertebrae and is limited cranially by the skull and caudally by the sacrum. 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 Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord:
    • Meningocele: only meninges Meninges The brain and the spinal cord are enveloped by 3 overlapping layers of connective tissue called the meninges. The layers are, from the most external layer to the most internal layer, the dura mater, arachnoid mater, and pia mater. Between these layers are 3 potential spaces called the epidural, subdural, and subarachnoid spaces. Meninges protrudes
    • Meningomyelocele: both meninges Meninges The brain and the spinal cord are enveloped by 3 overlapping layers of connective tissue called the meninges. The layers are, from the most external layer to the most internal layer, the dura mater, arachnoid mater, and pia mater. Between these layers are 3 potential spaces called the epidural, subdural, and subarachnoid spaces. Meninges and spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord protrude (most common NTD)
  • Open NTDs of the cranium:
    • Cranial meningocele: only meninges Meninges The brain and the spinal cord are enveloped by 3 overlapping layers of connective tissue called the meninges. The layers are, from the most external layer to the most internal layer, the dura mater, arachnoid mater, and pia mater. Between these layers are 3 potential spaces called the epidural, subdural, and subarachnoid spaces. Meninges protrude
    • Cranial encephalocele: both meninges Meninges The brain and the spinal cord are enveloped by 3 overlapping layers of connective tissue called the meninges. The layers are, from the most external layer to the most internal layer, the dura mater, arachnoid mater, and pia mater. Between these layers are 3 potential spaces called the epidural, subdural, and subarachnoid spaces. Meninges and brain stem Brain Stem The brain stem is a stalk-like structure that connects the cerebrum with the spinal cord and consists of the midbrain, pons, and medulla oblongata. It also plays a critical role in the control of cardiovascular and respiratory function, consciousness, and the sleep-wake cycle. Brain Stem/ cerebellum Cerebellum The cerebellum, Latin for "little brain," is located in the posterior cranial fossa, dorsal to the pons and midbrain, and its principal role is in the coordination of movements. The cerebellum consists of 3 lobes on either side of its 2 hemispheres and is connected in the middle by the vermis. Cerebellum/ cerebral cortex Cerebral cortex The cerebral cortex is the largest and most developed part of the human brain and CNS. Occupying the upper part of the cranial cavity, the cerebral cortex has 4 lobes and is divided into 2 hemispheres that are joined centrally by the corpus callosum. 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 Meninges The brain and the spinal cord are enveloped by 3 overlapping layers of connective tissue called the meninges. The layers are, from the most external layer to the most internal layer, the dura mater, arachnoid mater, and pia mater. Between these layers are 3 potential spaces called the epidural, subdural, and subarachnoid spaces. 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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