Congenital Diseases Associated With Central Nervous System

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: the brain the spinal cord the cranial and spinal nerves the eyes and other sensory organs the 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 4

What does the endoderm give rise to?

Answer 4

gut tube epithelium follicular cells of thyroid pancreas parathyroid liver Lungs (inner layers like bronchi) Thymus

Question 5

Derivatives of the neural tube details in an image

Question 6

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

Answer 6

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 7

What are the two modes of neural tube closure?

Answer 7

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 8

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

Answer 8

• 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 9

What is the process of convergence-extension?

Answer 9

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

Question 10

What is involved in the Wnt-PCP pathway?

Answer 10

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 11

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

Answer 11

Maternal diet:

• Vitamin deficiency/malnutrition
• Folate
• Inositol
• High levels of sugar

Maternal obesity

Diabetes

Hypertermia

Teratogenic agents

•Valproic acid (VPA)

Question 12

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

Answer 12

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 13

Summary of the lecture

Answer 13

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.

Question 14

Neural tube defects examples as a visual