14) embryology of the neural tube

derivations of the ectoderm

• nervous system

• sensory epithelia of the eye, ear, nose

• epidermis of skin and its appendages (hair and nails)

• mammary glands

• pituitary gland, enamel (ameloblasts), parotid

derivations of the mesoderm

• connective tissue (cartilage, bone, blood)

• striated and smooth muscles

• cardiovascular system

• genitourinary system

• spleen

• serous membranes lining the body cavities (pericardial, pleural, peritoneal)

derivations of the endoderm

• epithelial lining of the GIT, respiratory tract, bladder and urethra

• thyroid and parathyroid glands, liver, pancreas, submandibular gland

BMP-4

Ectoderm exposed to BMP-4 (from endoderm and mesoderm below) which develops into skin.

role of the primitive node

• The primitive node secretes BMP-4 antagonists: that allow a region of the ectoderm to develop into nerve tissue.

• Primitive node induces the development of notochord which in turn will induce the development of neural tube

BMP-4 and antagonist

Epidermis - develops as a response to BMP-4 agonist

Neural plate - does not develop into the epidermis due to BMP-4 antagonist

notochord

germ layer and position

• Mesodermal

• In the midline, forms the central axis

• In all chordates

function and remnants of the notochord

• Induces the development of the nervous system (main function then starts regressing)

• Remnants- nucleus pulposus in IVD

neurulation

formation/development of the neural tube

primary neurulation

function

Folding, elevation, closing and fusing of the neural tube along the dorsal midline

Results in the functional separation of the ectoderm and mesoderm forming non-neuronal tissue

Up to mid-lumbar enlargement of the spinal cord

primary neurulation

steps

• Notochord is the inducer

• Neural plate - ectodermal

• Neural groove and folds

• Neural folds fuse -> neural tube

where do neural crest cells come from

• Neural crest cells (dislodged cells from the neural folds)

  • Go everywhere from the cranial cavity to sacrum

neuropore

openings at the caudal and cranial end of the primitive streak which are in the process of closing

when do the neuropores close

The anterior neuropore closes around day 25.

The posterior neuropore closes around day 28.

somite

Somite made from mesoderm

Each somite develops into sclerotome (vertebral developments), myotome and dermatome

development of ventricles

Neural tube expands differently in its cranial and caudal ends

Cranial end - enlarge to form 3 primary brain vesicles

• subsequent enlargement to form secondary brain vesicles

Caudal end - stays tubular for the spinal cord

primary brain vesicles

secondary brain vesicles from the forebrain

secondary brain vesicles from the midbrain

secondary brain vesicles from the hindbrain

adult brain structures from the telencephalon

and neural canal regions

cerebrum: cerebral hemispheres (cortex, white matter, basal nuclei)

lateral ventricles

adult structures from the diencephalon

diencephalon (thalamus, hypothalamus, epithalamus)

Buds of the diencephalon smooths out to form the retina and optic nerve to the eyes

third ventricle

adult structures from the mesencephalon

midbrain

cerebral aqueduct

adult structures from the metencephalon

pons

cerebellum

fourth ventricle

adult structures from the myelencephalon

medulla oblongata

fourth ventricle

flexures of the brain

simple

flexures of the brain

not simple

neural tube

initial cell type

Initially lined by a single layer of pseudostratified cells - germinal layer (ependymal layer and epithelium of choroid plexus)

mantle layer of the brain

Some cells migrate to the mantle layer and stay there

• These develop into neuroblasts or glioblasts (supporting cells)

• Grey matter - neurones and neuroglia/glioblasts

marginal layer of the brain

Some glioblasts migrate further into the marginal layer

• Axons of neurones also migrate further

• White matter - axons and neuroglia/glioblasts

migration of the cells

diagram

neural tube → spinal cord

• Migration to form grey matter

• Migration to form white matter

• Posterior part develops sensory neurones

• Anterior part develops motor neurones

• pseudostratified layer of cells remains called the ependyma

cortical grey of the cerebrum and cerebellum

Neuroblasts migrate further outside forming cortical grey matter layer

pathologies associated with cortical neuronal migration

Pathologies associated with cortical neuronal migration can cause disorders e.g. autism spectrum disorder (ASD), epilepsy

neural crest cells

change in cell type

• At the time of neurulation, cells of the lateral most edge of the neural plate are induced to form neural crest cells

• Neural crest cells transform from epithelial cells to migratory mesenchymal cells (which are mesodermal) that contribute to forming many tissues in the body so are able to migrate

• Failure of migration gives rise to different types of abnormalities

embryological origin and migration of neural crest cells

main neural crest cell contributions

• Craniofacial skeleton

• All ganglia (sympathetic ganglia, parasympathetic ganglia…)

• Adrenal medulla

• Cardiac septa

• C cells of thyroid

• Pharyngeal arch contribution

• Odontoblast in teeth and deposition of dentine

NTDs

causes

• Maternal diabetes

• Maternal obesity

• Folic acid deficiency (main cause)

• Mutations in folate dependant or folate responsive pathways

• Antiepileptic drugs like valproic acid

Delayed or failure of closure of neural tube: usually defects in primary neurulation

what arises from secondary neurulation

Distal lumbar cord, conus medullaris and filum terminale

secondary neurulation

Medullary cord - new cord of cells in caudal end of embryo

• Gets canalised

• Two canals fuse and the cavity continues

secondary neurulation

position of spinal cord

At this point the spinal cord ends at the end of the coccyx.

• In adults spinal cord ends at lower border of L1

• In children spinal cord ends at upper border of L3

how does the spinal cord end up at the higher spinal levels

Shortening of medullary cord so it ends at lower border of L1

Conus medullaris and filum terminale forms

Dural sac is pulled up (regresses) - so long spinal nerves form

proposed theories of NTDs

• Neural tube fails to close: abnormalities in cellular behaviour (inefficient proliferation, disorganised cellular death and poor collective cell movement)

• Closed neural tube reopens: possibly due to a breakdown in critical cell-cell adhesion junctions

spina bifida

vertebral arch defect (may be said to be an NTD but is incorrect)

1 to 2/1000 live births world-wide

Failure of fusion of two vertebral arches

four types of spina bifida

-cele

Cystic mass

myelo-

nervous tissue

closed spina bifida

closed as skin is covering it

does not break through the skin

spina bifida occulta

• delayed or failure of closure of neural tubes AND vertebral arches fail to fuse

• Nervous tissue is still inside spinal canal

• Asymptomatic

• May just be seen as pathologies of that area (tuft of hair, dimple, excessive lordosis)

spina bifida occulta

x-ray

meningocele

 (spina bifida cystica)

• Fluctuating (as there's fluid which when touched moves) midline cystic mass covered with skin

• Only meninges protrude

• Spinal cord is still intact

• May be associated with neurological defects

• May develop defects like:

  • Weakness of legs

  • Trouble with bowel and bladder control

  These issues may change or progress as children grow

myelomeningocele

• Meninges and nervous tissue protrude

• Nervous roots gets stretched excessively

• Neural defects are always present

myelomeningocele

changes to the brain

Chiari II (downward herniation of the cerebellum through the foramen magnum)

Hydrocephalus (enlargement of the ventricles of the brain)

myeloschisis

spinal cord is exposed to the outside

diagnosis of spina bifida

• USG and blood test between 12 to 20 weeks

• Raised maternal serum alpha foetoprotein level in NTDs

alpha foetoprotein

• Alpha foetoprotein secreted from inside the neural tube

• The protein is in direct communication with the amniotic fluid so the maternal alpha foetoprotein blood levels increase

management of spina bifida

• In utero cellular therapies (human embryonic stem cell, pluripotent stem cells etc.)

• Foetal intervention/postnatal surgery

prevention of spina bifida

Daily 400 microgram folic acid supplement in addition to dietary sources for all women planning pregnancy till 12 weeks of pregnancy

further reading of neurological defects

DiGeorge syndrome

Congenital megacolon