Neural Tube Morphogenesis And Closure

Question 1

What are the four processes of neural tube development?

Answer 1

1. Induction.
2. Elongation.
3. Bending.
4. Closure.

Question 2

What is gastrulation?

Answer 2

Primitive groove is formed when epiblast ingress (via EMT) through primitive pit to form an endoderm at day 14/15 and mesoderm at day 16.

Question 3

What does gastrulation generate?

Answer 3

Trilaminar embryonic disk –> 3 layered embryo.

Formed in an anterior-posterior sequence.

Question 4

What does the epiblast form into?

Answer 4

Ectoderm.

Question 5

What happens to the primitive streak as the embryo grows?

Answer 5

It regresses.

Some cells migrate laterally to give rise to limb and mesoderm of GIT.

Question 6

How is the mesoderm initially arranged?

Answer 6

1. Cardiogenic area at cranial end (Mesoderm will then move caudally).
2. Below the cardiogenic area lies the prechordal plate (future mouth).
3. Centre (moving medial to lateral): Notochord, paraxial mesoderm, intermediate mesoderm & lateral plate mesoderm.
4. Cloacal membrane (future anus).

Question 7

Which direction does the primitive node travel when germ layers are laid down?

Answer 7

Caudal direction.

Question 8

What causes sirenomelia (Mermaid syndrome)?

Answer 8

A gastrulation defect that causes bladder & kidney defects.

Risk factor is increased insulin levels.

Question 9

What happens when the neural plate is induced within the epiblast?

Answer 9

1. Primitive streak regresses.
2. Primitive node and notochord induce neural plate, specified into 4 regions (forebrain, midbrain, hindbrain & spinal cord).
3. Neural plate becomes subdivided.

Question 10

What type of cells are present in the neural plate and primitive streak.

Answer 10

Neural plate = tall & thickened.

Primitive streak = squamous & cuboidal.

Question 11

How is the neural plate formed?

Answer 11

Induced by signals from the node and axial mesoderm (notochord & prechordal plate).

Axial mesoderm ingresses through the node, migrates in an anterior direction, underlying future nervous system.
Its migration releases Chordin (BMP inhibitor), blocking epidermal differentiation & promoting neural differentiation.

Question 12

Where is Chordin & BMP4 expressed?

Answer 12

Chordin: node & notochord.
BMP4: epidermis.

Question 13

What does the amniote node form into?

Answer 13

Forms dorsal mesoderm (notochord) when grafted into epiblast of 2nd gastrula, forming a 2nd embryo.

Hence node is an organiser.

Question 14

What 2 type of hinge points does primary neurulation produce?

Answer 14

Medial: bending at midline.

Dorsolateral.

Question 15

What does secondary neurulation lead to?

Answer 15

Remains of primitive streak form the medullary cord.
Medullary cord forms tubes.
Seen in lower sacral & caudal levels.

Question 16

How does neural tube closure occur, and in what day does it close?

Answer 16

Via convergent-extension (orientated cell division).
Day 22: 25% of spinal cord in a-p dimension.
Day23/24: it’s at 50%.
Day24/25: closed.

Question 17

How does the body axis narrow and elongate, which is essential for neural tube closure?

Answer 17

1. Convergent-extension (cells intercalate) via WNT-PCP pathway.
2. Planar cell polarity: E.g. Stereocilia in inner ear, all face in same direction. In mutation: randomly orientated.

In mutation: Neural tube is open.

Question 18

Where is elongation and narrowing of the body axis important?

Answer 18

Gastrulation.
Neural tube.
Kidney.
Cochlea.

Question 19

What are the 4 neural tube closure points and what defects do they cause?

Answer 19

Closure 1: hindbrain neuropore - craniorachischisis (defect in WNT-PCP signalling).
Closure 2: rostral neuropore - anencephaly.
Closure 3: anterior neuropore - anencephaly.
Closure 4: posterior neuropore - spina bifida.

Question 20

What is spina bifida?

Answer 20

Most common NTD, where spine fails to close properly.
Defect at/below lesion.
Unable to walk, lack of sensation, incontinence.

Causes other defects: hydrocephaly, gut & genital defects.
10% babies die in 1st year.

Treatment: in utero surgery before 24 weeks.

Question 21

What is spina bifida occulta?

Answer 21

Mild form, small gap in 1/more vertebrate of spine.
Often no nerve damage.
Appears with neurocutaneous signatures: pigmented mole, hairy tuft, angioma, lipoma, dimple.

In MRI: important to detect spot-tethered spinal cord.

Question 22

What is meningocele & myelomeningocele (spina bifida aperta)?

Answer 22

Occulta > aperta.
Meningocele: rare, meninges protrude through opening in spine. Doesn’t involve spinal cord - affected children can develop normally.
Myelomeningocele: severe, spinal cord and meninges protrude from spinal opening.
Permanent nerve damage and paralysis.

Question 23

What is anencephaly?

Answer 23

Head fails to close.

Question 24

What is Chiari type II malformations?

Answer 24

Cerebellum herniates, blocking fluid movements that leads to hydrocephaly.

Question 25

What is encephalocele?

Answer 25

The brain herniates out of the cranial fold into sac-like protrusion.
A sporadic event (50-75% isolated defect).

Question 26

What are the causes of NTD?

Answer 26

No clear cut, may be a genetic (Vangl2/Scribble mutation & sibling reoccurrence risk 2-5%) or environmental factor.

Question 27

What factors increase the risk of NTD in humans?

Answer 27

1. Carbamazepine & Fumonisin: inhibit folate uptake.
2. Trimethoprim: inhibit folate metabolism.
3. Valproic acid: 10x increased risk, disrupts GF regulation for neural development.
4. Hyperthermia/Hpothermia.
5. Maternal diabetes: increased neural cell death.
6. Obesity.

Question 28

In NTD cases, what is the status of folate metabolism?

Answer 28

Folate deficiency is NOT SUFFICIENT to increase NTD, but predisposes susceptible people.
Instead they show compromised folate metabolism.

Question 29

What is the evidence on MTHFR polymorphisms?

Answer 29

Can increase risk of NTDs in some population.

Question 30

Where is the messenger RNA for folate-binding protein 1 found and what is its function?

Answer 30

Found on points of neural tube closure and on extracellular surface of cells.
Functions in folate uptake and mutations cause NTDs defects.

Question 31

What are the 5 mechanism of folate action?

Answer 31

1. Methylation of DNA, protein, lipids.
2. X-inactivation.
3. Epigenetic changes to transcription.
4. DNA synthesis.
5. Protein synthesis.

Question 32

How can NTDs be diagnosed?

Answer 32

Increase in homocysteine in mother’s blood.

Increase in maternal serum alpha-fetoprotein.

Question 33

What is inositol thought to prevent?

Answer 33

Prevents NTDs.
Deficiency is associated with NTDs.
Appears to be safe: already being used in psychiatric disorders (autism, depression,), polycystic ovary syndrome, respiratory distress syndrome.

No evidence it increases uterine contractions (inositol thought to mimic oxytocin which can cause miscarriages).

Question 34

What is the PONTI trail?

Answer 34

Women planning pregnancy (previous NTD child).
To see if there was a difference in reducing risk of NTDs with folic acid + inositol / folic acid + placebo.
Through ultrasound pregnancy outcome & inositol assay in urine samples.

Question 35

What does the neural crest form?

Answer 35

Lateral edges of neural plate, at boundary with epidermis.

Crest cells delaminate from neural tube & migrate away.

Question 36

What type of cells are neural crest cells?

Answer 36

Pluripotent (form cranial & trunk neural crest cells).

Are migratory.

Question 37

What are examples of neurofibromatosis?

Answer 37

Von Recklinghausen Disease (peripheral nerve tumour).

Charcot-Marie-Tooth (demyelination syndrome).

Question 38

What are examples of pigmentation defects?

Answer 38

Waardenburg syndrome type 1 & 11.

Albinism.

Question 39

What is pheochromocytoma?

Answer 39

Tumours of chromaffin cells of suprarenal medulla.

Question 40

What is Hirschsprung disease?

Answer 40

Absence of enteric ganglia.