Neuroembryology

NEUROSCIENCE 1 Edgardo Tan, MD

1B | August 17, 2017

Recordings from Dr. Tan’s lecture and PowerPoint Presentation Neurulation

Excerpts from Textbook (Fundamental Neuroscience for Basic and Clinical Applications
– Haines, 4th Edition) - Process by which the neural plates folds over on itself and
Larkie (Class of 2017) Notes fuses in a zipper-like fashion to become a neural tube
- Neural Plate à Neural Groove à (fusion that starts at the
USE AT YOUR OWN RISK cervical area) Neural Tube

CNS Development
- Embryogenesis
o Induction
o Neurulation
o Vesicle formation
o Ventricular system
o Choroid plexus
- Histogenesis
o Cellular differentiation (proliferation and migration)
o Cellular Maturation

Pre-embryonic / Conceptus Period

st nd
- 1 to 2 week
- Not susceptible to teratogenic environment because they will
die (spontaneous abortion is common)
rd th
3 to 4 Week
- Gastrulation
- Most important
- CNS starts to develop (from the neural tube)

Embryonic Period
rd th
- 3 to 8 Week
- Anything that will happen may cause major morphologic
abnormalities

Fetal Period
th
- 9 Week onward
- Functional defect and/or minor morphologic abnormalities

Ectoderm
- Neural ectoderm – CNS, PNS
- Surface ectorderm - Epidermis
- Neurocutaneous syndrome (Phakomatoses) – Skin
o Primary Neurulation
manifestation of a CNS problem
§ Process by which the brain and most (cervical,
thoracic, upper lumbar) of the spinal cord are
Mesoderm + Endoderm à other organs and organ systems formed
§ Begins when the notochord induces the overlying
EMBRYOGENESIS embryonic ectoderm to form a neural plate
th th
§ 17 to 18 day
Induction
§ Neural tube must be closed off from CSF
- Start of embryogenesis
§ Neural Crest Cells à PNS
- Process of cell to cell signaling to undergo changes
§ Neural Tube à CNS
- Underlying mesoderm induces the ectoderm to become the
§ Somites simultaneously grows with the neural tube
future neural ectoderm and form the neural plate, giving rise § Day 24 – Ant. Neuropore closure
to most of the nervous system § Day 26 – Post. Neuropore closure
- Takes place in the ectoderm of the head process overlying § Neural folds come together in the cervical region
the notochord and fuse; closure then proceeds in a rostral and
- Due to hormones, neurotransmitters, and growth factors caudal direction
th th
- 16 to 17 day
§ Requires folate (folic acid) for proper nervous
system development
Notochord
• Taken 1 month before conception and
- Directs the overlying ectoderm to form the neural plate
continuing through the first trimester
(neural ectoderm)
• For prophylaxis: 400 mcg (0.4 mg) / day
- Defines the longitudinal axis of the embryo (by production of
cell adhesion molecules) • For those with family history or a member who
- Determines the orientation of the vertebral column has history of spina bifida: 4000 mcg (4.0 mg) /
- Persists as the nucleus pulposus of the intervertebral disks day
• Cofactor in converting homocysteine to
methionine

Transcribed by Stephen Antonio 1

 NEUROSCIENCE 1 Neuroembryology – Edgardo Tan, MD

• Homocysteine accumulation is teratogenic § The malformation of the spinal cord

• Folate deficiency à Spinal Dysraphism (Spina results in a portion of the brain stem
Bifida) and/or cerebellum to be pulled into the
• Anti-convulsants (ex. Carbamazepine, vertebral canal (Arnold-Chiari
valproate, lamotrigine, phenytoin, gabapentin, Malformation). This inhibits egress of
topiramate, levetiracetam) can prevent folic CSF into the subarachnoid space
acid from being utilized à Higher incidence of where it is absorbed into the venous
spina bifida system
o Secondary Neurulation § Multiple neural tube defects can occur in the same
§ Process by which the caudal parts of the spinal individual
cord (lower lumbar, sacral, and coccygeal o Defects of Secondary Neurulation
segments) are formed § “Myelodysplasias”
• In humans, most of the coccygeal spinal § Tethered Cord Syndrome
segments regress • Spinal cord cannot go continuously upward
th
§ 26 Day • Spinal cord usually ends at L3
§ Independent from the neural tube • Hypertrophied filum terminale à continues to
§ Canalization and retrogressive differentiation tether
(Synonym: Secondary neurulation) • Low conus medularis (because the spinal cord
§ Caudal Eminence – mass of cells that develop in is being dragged down)
the caudal part of the neural tube and it enlarges • Can be attached to fat
eventually becomes continuous with the neural tube (lipomyelomeningocoele)
• Large, canalized, and fused with the neural • Manifestations:
tube o Weakness of both lower extremities
• On Day 20, a mass of mesenchyme (caudal o Sensory loss
eminence) condenses, hollows out and then o Asymmetric growth of legs and feet
joins with the neural tube formed by primary o Problems with bladder/bowel control
neurulation by Day 40. o Others: Scoliosis, External signs in the
§ Filum Terminale – thickened filum that attaches to skin (tuft of hair, dimple, etc.)
the coccyx holding the spinal cord
Primary Neurulation Secondary Neurulation
o Defects of Primary Neurulation - Starts from ectoderm - Starts from mesenchyme
§ “Dysraphic Defects” (neural tube) (caudal eminence)
§ Anterior Neuropore’s failure to close (depends on - Folds to form a tube - Cochrndenses, the
the degree and size of malformation) hollows
• Anencephaly - Undergoes an epithelial
o No brain and no skull transition
o Usually not compatible with life Dysraphic defects Myelodysplasias
o Can be born alive and live for several - Ant. Neuropore: - Tethered cord syndrome
hours or days Anencephaly,
o Brainstem and spinal cord formation is Encephalocoele, Chiari
normal malformation
o 1 in 1,500 births; 4x common in females - Post. Neuropore:
• Encephalocoele / Meningoencephalocoele Myeloschisis, Spina bifida
o Sac-like protrusions of the brain and the (oculta, aperta, cystica)
membranes that cover it
o Content of the sac can be pure fluid or Neural Crest
brain tissues or even parts of the ventricles - Specialist cells that moves out from the neural tube
o Caucasian / European: Occipital - Responsible for PNS
o Asian: Frontal - All ganglia (group of neurons outside the CNS) are derived
• Chiari Malformation from neural crest except basal ganglia (misnomer; basal
o Cerebellar tonsils herniate and pushes into ganglia is inside the brain/CNS)
the spinal cord
§ Posterior Neuropore Principal Structures Derived from Neural Crest Cells
• Myeloschisis / Rachischisis Neural Elements Non-Neural Elements
o Worst kind - Post. root ganglia - Schwann cells
o Exposed spinal cord - Paravertebral (symp. - Melanocytes
o Exposed neural element without skin as chain) ganglia - Odontoblasts
covering (directly into the atmosphere) - Prevertebral (preaortic) - Satellite cells of peripheral
• Spina Bifida (Oculta, Aperta, Cystica) ganglia ganglia
o Neural tube closure can fail at any point - Enteric ganglia - Cartilage of pharyngeal
along the neuraxis - Parasymp. ganglia of CN arches
o Failure of the bony element to close VII, IX, X - Ciliary and pupillary
o Spina Bifida Oculta – cannot be seen - Sensory ganglia of CN V, muscles
outside, felt upon palpation VII, VIII, IX, X - Chromaffin cells of the
o Meningocoele – meninges herniate with adrenal medulla
CSF - Pia and arachnoid of the
o Meningomyelocoele – with spinal cord meninges

Transcribed by Stephen Antonio 2

 NEUROSCIENCE 1 Neuroembryology – Edgardo Tan, MD

Three-Vesicle Stage Brain Flexures

- Origin of Neural Tube - Sulci, gyri
th
- 4 Week - Infoldings
- Prosencephalon – forebrain - In order to increase surface area
- Mescencephalon - midbrain - To accommodate more surface
- Rhombencephalon – hindbrain
Primary Brain Vesicles
Five-Vesicle Stage - Cervical Flexure
th
- 5 Week o Neck area
- Prosencephalon à Telencephalon (Cerebral Hemisphere) o Appears at the junction of the hindbrain
+ Diencephalon (Diencephalon, Optic Nerve and Retina) (rhombencephalon) and the spinal cord flexing ventrally
- Mescencephalon à Mescencephalon (Midbrain/Brainstem) in a concave manner
- Rhombencephalon à Metencephalon (Cerebellum, Pons) + - Midbrain / Mescencephalic Flexure
Myelencephalon (Medulla) o “Cephalic Flexure”
o Develops in the region of the midbrain flexing ventrally
in a concave manner

Secondary Brain Vesicles

- Pontine Flexure
o Appears in the region of the developing pons flexing
ventrally in a convex manner
o Myelencephalon and metencephalon
- Telencephalic Flexure
o “Diencephalic-Telencephalic Sulcus”
o Divides the forebrain into the diencephalon caudally and
the telencephalon rostrally

Telencephalic Flexure

th
At the end of the 5 week AOG:
- Telencephalon
o à Cerebral cortex and the subcortical while matter
(including internal capsule), the olfactory bulb and tract,
portions of the basal ganglia, the amygdala, and the
hippocampus
- Diencephalon
o à Thalamic nuclei and associated structures and also
to the optic cup (optic nerve and retina)

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 NEUROSCIENCE 1 Neuroembryology – Edgardo Tan, MD

Cavity inside the neural tube is forming during the vesicular
stages:
- Telencephalon à Hemisphere à 2 Lateral Ventricles
- Diencephalon à Third Ventricle (Interventricular Foramen
of Monro)
- Midbrain à Aqueduct of Sylvius (Iter)
- Metencephalon à Pons and Cerebellum +
Myelencephalon (Medulla) à Fourth Ventricle
o Foramen of Magendie - Midline
o Foramen of Luschka - Lateral
Choroid Plexus Development
- Responsible for CSF production
- Develops in the floor and roof the lateral ventricle, and roofs
of the third and fourth ventricles by a process of invagination
of blood vessels
- Formed by a core of blood vessels surrounded by pia which
is adherent to the ependymal lining of the vesicles
- Develops where pia mater and ependymal are in direct
contact
- Iter – no contact with Choroid Plexus

Meningioma – Tumor from the meninges

- Arachnoid cap cell/layer
- Intraventricular Meningioma
o As vessels form the choroid plexus, it brings some
layers/coverings and are retained

Somite Differentiation
- Cranial-to-caudal formation
- Day 20 to 35
- Sclerotome à Bone and cartilage
- Dermomyotome
o Dermatome à Dermis
o Myotome à Skeletal muscle
Three-Vesicle Five-Vesicle Adult Structure
Stage Stage (Maturation) Neural Ectoderm:
th
(4 Week)
th
(5 Week) - Neuroblastic – Forms neurons
Prosencephalon Cerebral 2 lateral - Glioblastic – Forms supporting cells (glial cells – hugs the
(Telencephalon hemisphere ventricles axons of the CNS for insulation)
and and Third Ventricle o Astrocytes
Diencephalon) diencephalon (Foramen of o Oligodendroglia
(Prososcele) 2 lateral telocele Monro) o Radial glial cells
Median telocele o Ependyma
Diocele
Mescencephalon Midbrain Aqueduct of Microglia – from mesoderm
(Midbrain) Mesocele Sylvius
(Mesoscele) (Iter) Neural Tube
Rhombencephalon Pons and Fourth Ventricle - Gives rise to the CNS
(Metencephalon cerebellum (Foramen of - Rostral 2/3 gives rise to the brain
and Medulla Magendie) - Caudal 1/3 gives rise to the spinal cord up to the lumbar
Myelencephalon) Metacele (Foramina of levels
(Rhombocele) Myelocele Luschka) - Caudal eminence gives rise to the sacral and coccygeal
segments
Abnormalities
- Congenital Hydrocephalus Neural Crest
o From birth - Gives rise to the PNS
o Congenital aqueductal atresia - Melanocytes
o Block of the iter - Schwann cells
- Dandy-Walker Malformation - CNs ganglia (5, 7, 9, 10)
o Poster fossa malformation - Autonomic ganglia (Postganglionic symp. neurons)
- Neurons and satellite cells of symp. ganglia
Defects of Prosencephalization - Dorsal root ganglia
- Prosencephalon (Forebrain) is developed with the facial - Arachnoid and pia mater (leptomeninges)
features - Adrenal medulla
- “The more sever the brain malformation, the more severe the - Chromaffin tissue
facial defect.”
- Holoprosencephaly - single-lobed brain HISTOGENESIS
o Alobar Holoprosencepaly – No corpus callosum
o Semilobar Holoprosencephaly – Incomplete forebrain - Cellular Differentiation
division - Cellular Migration and Maturation
o Reults from a failure of cleavage of the embryonic
prosencephalon by Day 35 Cellular Differentiation
o One telecephalon and one diencephalon - Radial glia – serve as transient cell guide for cell migration
- Environmental exposusres to alcohol, retinoic acid, and o Forms astrocytes after cell differentiation and migration
maternal diabetes - Three distinct layers:
- Syndromic disorders as Trisomy 13 and 18 o Ependymal or Ventricular Zone – most of the cells of
- Gene defects SHH 7q36 the neural tube multiplication happens here
- TORCH o Intermediate (Mantle) – primordia of future gray matter
- HIV o Marginal – primordia of future white matter

Transcribed by Stephen Antonio 4

 NEUROSCIENCE 1 Neuroembryology – Edgardo Tan, MD

- Growth spurts: Extracellular Matrix Molecules

th th
o 10 to 18 week AOG – vulnerable to irradiation, - As guide to reach the correct targets
chromosomal anomalies, and viral infections (TORCH, - Fibronectin and Laminin contain amino acid sequence
etc.) leading to various abnormalities in the heart, brain, Arginine-Glycine-Aspartate (RGD) recognized by Integrins
and eyes on the surface of neural crest cells
th nd
o 30 week AOG extending through 2 year of life – - Cell-to-Cell Interactions – Molecular signal
sensitive to factors such as malnutrition (genes/proteins) generated by the target cell induced by
growth cone to form the synapse of the target cell
Spinal Cord Development
- Neural tube divides into two: Dermatomal Level – If you have a deficit at a certain
o Dorsal (Upper) Alar Plate – sensory neurons dermatomal level, you’ll know that at that level of spinal cord
o Ventral (Lower) Basal Plate – motor neurons you have a problem
- 3 layers: Marginal, Mantle, Ependymal
- Sulcus Limitans – imaginary line Vertebra à Spinal Cord
- Central Canal - canal - Terminal end of the spinal cord is attached a certain level of
- Anterior portion sends neurons outwards for motor the sacral vertebra
- Dorsal Root Ganglion sends process going to the spinal cord - Vertebra and spinal cord grows fast
for sensory - Vertebra grows upward, spinal cord goes upward
- At the brainstem: - Spinal cord cannot catch up since it’s held by the nerve roots
o Sensory – lateral / outer à Growth of vertebra is faster than spinal cord
o Motor – medial / middle - Cauda equina - Long nerve at the caudal section of the
spinal cord (horse hair-like)
Important Acronyms in Topics regarding Brainstem - Spinal cord ends at L3 (clinical significance on lumbar
- Somatic Efferent, SE: Skeletal muscle puncture)
- Visceral Efferent, VE (autonomic ganglia):
o Intermediolateral Cell Column – T1-L2 Brainstem Development
o Sacral Visceromotor Nucleus – S2-S4 - Sensory – lateral / dorsal
- Somatic Afferent, SA: Skin, receptors in joint capsules, - Motor – medial / ventral / basal
tendons, and muscles
- Visceral Afferent, VA: Visceral structures like stomach Medulla Oblongata – CN 12, 11, 10, 9
Myelencepahlon Medulla
Neural Tube Spinal Cord Neural Cavity à Central canal
Neural Cavity Central canal Fourth Ventricle
Ventricular Zone Ependymal cells Alar Plate à Vestibular/Cochlear (VIII) Nuclei
Alar Plate Dorsal gray horn (Sensory) Solitary Nucleus (GVA, SVA) –
Basal Plate Ventral gray horn (Motor) swallowing, saliva
Lateral gray horn Spinal Trigeminal Nucleus (GSA)
Marginal Zone White matter Nucleus Gracilis and Cuneatus
Inferior Olivary Complex (Cerebellar
Gray matter (H-shaped) grows from the center, with the white relay nuclei)
matter surrounding it. à Reverse in the cortex where the Basal Plate à Hypoglossal Nucleus (GSE)
cortical cell (gray) outside, white matter inside. Nucleus Ambiguus (SVE of CN IX, X,
XI)
Functional Components: Inf. Salivatory Nucleus (IX) (GVE)
- Basal Plate Dorsal Motor Vagal Nucleus (X) (GVE)
o Anterior Horn motor neurons à skeletal muscle (SE)
full length of spinal cord Pons – CN 8, 7, 6, 5 (mesencephalic nucleus, spinal nucleus,
o Lateral Horn motor neurons à autonomic ganglia (VE) trigeminal ganglion proper, spinal ganglion)
extends from T1 – L2 (intermediolateral cell column) and Metencephalon Pons and Cerebellum
from S2-S4 (sacral visceromotor nucleus) Neural Cavity à Fourth Ventricle
- Alar Plate Alar Plate à Cerebellum
o Receipved the central processes of Posterior Root Sensory Nucleus of V (GSA)
Ganglion from skin, receptors in joint capsules, Vestibular/Cochlear Nuclei (SSA)
tendons, muscles à SA Solitary Nucleus (SVA of VII)
o From the visceral structure such as stomach à VA Pontine Nuclei (Cerebellar relay
nuclei)
As neural tube is maturing, the neural crest cells are maturing Basal Plate à Trigeminal Motor Nucleus (SVE)
and dividing. Facial Nucleus (SVE)
Abducens Nucleus (GSE)
At the same level where your neural tube is developing as the Superior Salivatory Nucleus (VII)
spinal cord, the neural crest cells (somites) divides: (GVE)
- Dermatome – skin
- Sclerotome – bone
- Myotome – muscle

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 NEUROSCIENCE 1 Neuroembryology – Edgardo Tan, MD

Midbrain – CN 1, 2 Diencephalon
Mesencephalon Midbrain - Hypothalamus
Neural Cavity à Sylvian Aqueduct of Iter - Thalamus
Alar Plate à Superior and Inferior Colliculus Nuclei o Outside First Sequence – Grows outside first
Red Nucleus o Radial glial cells grow up and down, some stay outside;
Substantia Nigra when folded there is a second layer, third layer
Basal Plate à Oculomotor Nucleus (GSE) o Geniculate ganglion develops first before the
Trochlear Nucleus (GSE) dorsomedial nuclei
Edinger-Westphal (EWpg) Nucleus o Orderly map of the sensory world
(GVE) § Lateral geniculate – part of the visual pathway
§ Medial geniculate – part of the auditory pathway
Rhombomeres § Ventral posterolateral nucleus – somatosensory
- Clusters of immature cells separated by thin bands of - Epithalamus – pineal gland, habenular nuclei, stria
neuroepithetial cells medullaris
- Segmentation and regionalization
- 8 segments: Each rhombomere has assigned part
o r1 – Mesencephalon
o r8 – Medulla
- Genes that will the
neural tissues in that
area that they are
confined in that
segment
- Neuromeres –
located at the spinal
canal

Metencephalon
- Develops into 2
structures
- Pons and cerebellum

Cerebellum
Development
- Derivative of metencephalon
- Thick area of Rhombomere 3 (r3) à Cerebellum
o Divides and grow; Produces lots of infoldings to
accommodate the fast growing
- Cerebellum – important for coordination of motor cells
- Postero-lateral Fissure
o Forms first
o Divides tissues into flocculonodular lobe and cerebral
Cerebral Hemisphere
body of the cerebellum body
- Inside-Out Pattern
- Primary Fissure
o First grows inside, then goes outward; Folding à 6
o Divides cerebellum body into anterior and posterior
layers
lobes
o Oldest layer: Layer 1
- Neurons of the cerebellum are derived from neuroblasts in
o First wave: Layer 6
the ventricular zone of the cerebellar primordium forming the
o First cells to migrate disembark and take positions close
deep cerebellar nuclei (responsible for the coordination of
to ventricular surface
movement: lateral à Dentate, Emboliform, Globose,
- Early development of the cerebral cortex
Fastigii ß medial) and the Purkinje and Golgi Cells
o The nuclei of the neuroblasts undergo a cycle of
- Three layers
outward and inward migration as the neuroblasts
o Molecular layer
progress through their cell cycle (G1 – first gap phase; S
o Purkinje layer
– DNA replication; G2 – second gap phase; M – mitosis
o Granular layer
and cytokinesis)
- Outside-In pattern – grows outside, then goes inside
Formation of the Cerebral Cortex
- All of them comes from the cortical plate
- Formation of cortical plate at interface of marginal zone and
intermediate zone
- Formation of subplate – a narrow region internal to cortical
plate
- Marginal zone gives rise to layer 1
- Cortical plate gives rise to layers 2-6
- Subplate and intermediate zone (internal cortical plate)
give to subcortical white matter

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 NEUROSCIENCE 1
Brain Fissure Development
- Normal amount of sulci
- At the peak of period of cellular migration:
o Hemispheric fissures (sulcus, gyrus-brain parenchyma)
appear and mold the telencephalic surface into gyri and
sulci that demarcate different cortical convolutions and
lobes. This is due to local variation in the rate of growth
st
- 1 Trimester:
o Longitudinal cerebral, Sylvian, and transverse cerebral
fissures are recognizable
- The secondary sulci are completed by 32 weeks AOG
o The central (Rolandic) and calcarine sulci appear
between 24 and 26 weeks of gestation
- Tertiary sulci completed during the last month of gestation
o The formation of the cortical gyri proceeds rapidly near
th
the 30 week of gestation
o The Entire hemisphere surface is gyrated by 32 week
nd
of gestation
Abnormalities of Cortical Development
- Lissencephaly
o Failure of neuronal migration
o Smooth surface
o Gyri fails to form
rd th
o 3 to 5 month of gestation
- Pachygyria – big gyri, few sulci
- Microgyria – small gyri, many sulci
o Prone to develop mental abnormalities, high sensitivity
to seizure
- Heterotopia – migration of the immature cells that got
trapped when they travelled
- Schizencephaly
o Split brain
o Results from either an early vascular accident or a
mutation in the homeobox gene, EMX2
o Porencephaly – due to a brain destruction à forming a
cystic cavity
Three Important Parameters in brain organization that
determine brain functions:
1. Density of neurons*
2. Pattern of axon and dendritic branching*
3. Pattern of synaptic contacts – occurs throughout life
(remodeling)
* Determined within the first 2-3 years after birth
Overproduction of Neurons and Apoptosis
- Apoptosis – genetically programmed cell death; active
cellular process
o Elimination of redundancy in number of neurons
o Regulation of neural connectivity, matching the size of
input population of neurons with the number or size of
target population
Transcribed by Stephen Antonio
Neuroembryology – Edgardo Tan, MD
Cellular Events in Brain Development
- Axonal Outgrowth
o Growth cones guided by tropic (target place) and
trophic (metabolism maintenance) factors
o By interacting with the environment, it finds signals that
guide the axon to connect with its target cells
o Growth factors (nerve growth factor, brain-derived
neurotrophic factor, fibroblast growth factor) limit cell
death
- Synaptogenesis
o Biochemical and morphologic changes
o Presynaptic and postsynaptic terminals
o Concept of synaptic stabilization
§ Signal generated by the presynaptic cell (NEs)
§ Means for the postsynaptic cell to respond to the
presynaptic signal (requires the right cues from
target cell)
§ A “retrograde signal” from the postsynaptic cell to
the presynaptic cell to indicate which contacts are
to remain in maturity
- Plasticity and Competition
o Plasticity
§ Alterations in selective neuronal death and axonal
simplification and to the retention of transient
axonal branches and synapses that would
otherwise be lost
§ Ex. Visual Connection à Amblyopia (eye fails to
achieve normal visual acuity, even with prescription
eyeglasses or contact lenses)
o Critical period varies from region to region and has
clinical implication
o Axonal and synaptic development are especially
vulnerable to perinatal hypoxia, malnutrition, and
environmental toxins
- Myelination
o Oligodendrocytes myelinate neuronal axons (1:40
th
axons) in the CNS (begins at 6 month of development
st
and peaks between birth and 1 year of life until
adulthood)
§ Delay result in a delay in functional development
o Faster transmission due to saltatory conduction
o Neurodegenerative diseases (leukodystrophies) affect
myelin formation
o Inborn errors of amino and organic acid metabolism
impair myelination (phenylketonuria)
o Malnutrition also impair myelination
o PNS: Schwann Cell (1:1 axon)
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