Congenital Diseases Associated with Central Nervous System Flashcards
What is the first step in the formation of the central nervous system?
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.
What does the ectoderm give rise to?
Our nervous system, epidermis, eye lens, mouth, and inner ear derive from the ectoderm.
What does the MESODERM give rise to?
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
What does the endoderm give rise to?
gut tube epithelium follicular cells of thyroid pancreas parathyroid liver Lungs (inner layers like bronchi) Thymus
Derivatives of the neural tube details in an image
What is the Wnt/PCP pathway essential for with regards to the neural plate?
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
What are the two modes of neural tube closure?
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)
What are the cellular and molecular mechanisms involved in primary neurulation?
- 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
What is the process of convergence-extension?
A process of lengthening by narrowing, which requires cells to become polarized, in the plane of the cell layer
What is involved in the Wnt-PCP pathway?
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
What environmental factors are associated with Neural Tube Defects (NTD)?
Maternal diet:
- Vitamin deficiency/malnutrition
- Folate
- Inositol
- High levels of sugar
Maternal obesity
Diabetes
Hypertermia
Teratogenic agents
•Valproic acid (VPA)
What is the only known intervention preventive for any congenital anomaly?
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
Summary of the lecture
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.
Neural tube defects examples as a visual
