Congenital diseases associated with CNS

Question 1

What is the first step in the formation of the central nervous system?

Answer 1

→ The formation of the neural plate, and its folding to give rise to the neural tube.
→ The neural tube will then differentiate into the following structures:
1. Brain
2. Spinal cord
3. Cranial
4. Spinal nerves
5. Eyes and other sensory organs
6. Neural crest

→ Defects in neural tube formation will affect the formation of some or all of these structures.
→ In humans, neurulation occurs between weeks 3 and 4.
→ The neural plate is initially a flat sheet of cells located along the dorsal portion of the developing embryo, in direct continuation with the epidermis, and exposed to the extraembryonic medium.
→ This sheet of cells will become a tube, and will end up being located inside the embryo.
→ Neurulation- process of the neural tube forming
→ As the neural tube closes, it becomes patterned along the dorso-ventral and the rostro-caudal axes.
→ This process is driven by secreted signalling molecules, which promote the specification of different CNS structures along each axis.

Question 2

What does the ectoderm give rise to?

Answer 2

Our nervous system, epidermis, eye lens, mouth, and inner ear derive from the ectoderm.

Question 3

What does the MESODERM give rise to?

Answer 3

M uscle (skeletal, cardiac, smooth)
E ndothelium of our blood vessels
S pleen
O varies and other gonads
D ducts of genital system
E ndothelium of our lympathic vessels
R enal for the kidneys
M ale gonads

Question 3

What does the endoderm give rise to?

Answer 3

1. Gut tube epithelium
2. Follicular cells of thyroid, pancreas, parathyroid, liver 3. Lungs (inner layers like bronchi)
3. Thymus

Question 4

Derivatives of the neural tube details in an image

Question 5

What is the Wnt/PCP pathway essential for with regards to the neural plate?

Answer 5

→ The Wnt/PCP pathway is essential for the shaping of the neural plate prior to closure, by modulating the medio-lateral convergence and anterior-posterior extension of this tissue.
→ Studies in mouse models have shown that in the absence of Wnt/PCP activity, the neural plate remains unusually broad and the subsequent steps in neural tube closure (bending and fusion) do not occur efficiently

Question 6

What are the two modes of neural tube closure?

Answer 6

Primary neurulation:
*rolling-up of tube
*closure is by fold apposition then “zipping-up”
*Finally, at cranial and caudal neuropores

Secondary neurulation: (occurs at the most caudal end of the neural tube)
*tunnelling or hollowing of tail bud

*The primary and secondary neural tube become continuous, this point is located at: somites level 30-31 in human (2nd sacral)

Question 7

What are the cellular and molecular mechanisms involved in primary neurulation?

Answer 7

→ Shaping of the neural plate occurs by convergence/extension
→ Tubing requires bending at hinge points
→ Cell wedging at hinge points: microtubules & actin filaments

The above are controlled by the Planar Cell Polarity pathway

Question 8

What is the process of convergence-extension?

Answer 8

A process of lengthening by narrowing, which requires cells to become polarized, in the plane of the cell layer

Question 9

What is involved in the Wnt-PCP pathway?

Answer 9

Wnts: secreted signalling molecules – the ligand
Frizzleds: Wnt receptor, transmembrane proteins
Vangl and Celsr: co-receptors necessary for signal transduction
Dvl1-3: cytoplasmic proteins, activated upon interaction between Wnts and Fzds

Mouse mutants in components of the Wnt-PCP pathway show neural tube defects:
→ celsr1-/- (crash)
→ vangl-/- (loop-tail)
→ scribble-/- (circletail)
→ dvl1/2
→ fzd3/6

WNT/planar cell polarity (PCP) signaling pathway controls tissue polarity and cell movement

→ Mouse mutants in the Wnt-PCP pathway cause craniorachischisis
→ The neural plate is abnormally broad with a non-bending region between neural folds - leading to chraniorachischisis

Question 10

What environmental factors are associated with Neural Tube Defects (NTD)?

Answer 10

→ Maternal diet:
*Vitamin deficiency/malnutrition
*Folate
*Inositol
*High levels of sugar

→ Maternal obesity

→ Diabetes

→ Hypertermia

→ Teratogenic agents
*Valproic acid (VPA)

Question 11

What is the only known intervention preventive for any congenital anomaly?

Answer 11

Folic acid supplementation/fortification

→ Probably no adverse effects
→ Suggested problems: B12 deficiency (reduce detection by masking anaemia, allowing neurotoxic complications); promotion of colon polyps to cancer - both not confirmed
→ Also reduces palate & heart defects
→ Up to ~70% (?) of NTD can be prevented by folate

But there are still NTDs that cannot be prevented by folate (“folate resistant NTD”)

Inositol:
→ Can prevent NTDs in experimental models
→ Current clinical trials, still insufficient evidence for a protective effect in humans

Question 12

Summary of the lecture

Answer 12

→ Neurulation is the process by which the neural tube forms during embryogenesis.
→ Neurulation happens during weeks 3 and 4 in humans - very early on, often prior to the woman knowing that she is pregnant.
→ Defects at any step during neurulation will have profound consequences for the formation of the CNS - often incompatible with life, or leading to severe disability.
→ The Wnt-PCP pathway is one of the main molecular players driving neurulation.
→ A combination of genetic and environmental factors influence neurulation.
→ Folic acid has been shown to prevent up to 70% neural tube defects, although its mechanism of action is still not fully understood.