Congenital Diseases Associated with Central Nervous System Flashcards
What is neurulation?
Neurulation is a process in which the neural plate bends up and later fuses to form the hollow tube that will eventually differentiate into the brain and the spinal cord of the central nervous system.
The role of the Wnt/PCP pathway
How does the closure of the neural tube occur?
- Involves the elevation of the edges of the neural plate to form the neural folds
- The formation along the midline called the neural groove
- The neural folds will move towards the midline and fuse forming a tube
Where are the different closures of the cranial and caudal neuropores?
Closure 1 happens at the edge between the hind brain and spinal cord
Closure 2 happens between the hindbrain and the forebrain
Closure 3 happens at the most rostral portion of the forebrain
Closure 4 occurs more rostrally within the hindbrain than closure 1
Closure 5 is located at the very posterior portion of the neural plate
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 region of the neural tube
- tunnelling or hollowing of tail bud
The primary and secondary neural tube become continuous
- At the level of somites 30-31 in human (2nd sacral)
What are the cellular and molecular mechanisms that occur during 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
Controlled by the Planar Cell Polarity pathway
What happens during convergence-extension?
A process of lengthening by narrowing, which requires cells to become polarized, in the plane of the cell layer
So the tissue narrows but elongates in the anterior-posterior directions
What does the Wnt-PCP pathway have to do with neurulation? What happens when there are defects in this pathway?
Wnts: secreted signalling molecules – the ligand
Frizzleds: Wnt receptor, transmembrane proteins
Vangl and Celsr: co-receptors necessary for signal transduction
Dvl1, 2 and 3: cytoplasmic proteins, activated upon interaction between Wnts and Fzds
- These proteins along with other proteins will lead to the regulation of transcription and also cell cytoskeletal regulation
Mouse mutants in components of the Wnt-PCP pathway show neural tube defects:
- celsr1-/- (crash)
- vangl-/- (loop-tail)
- scribble-/- (circletail)
- dvl1/2
- fzd3/6
In all these cases the neural plate is abnormally broad with a non-bending region between neural folds - leading to craniorachischisis
What is cell wedging and apical constriction?
Cell wedging is the mechanism by which the hinge points, that are the places where the neural plate folds are being formed
It involves changes in the shape of the cells in the neural plate so the apical side becomes very narrow
This change in their shape is what allows the folding
The process of apical constriction of the cell is driven by the remodeling of the cell cytoskeleton at the apical cortex of the cell
What happens in the apical region of epithelial cells?
Cells in an epithelium have apico-basal polarity
At the apical region of the cells you have these tight arrays of actin filaments which is what are remodelled when the cell changes shape
The Wnt-PCP pathway localizes actomyosin to the apical surface, in a mediolateral polarized way so that is becomes contracted along the mediolateral axis
What are the main neural tube defects in humans?
Anencephaly: cranial neuropore failure
- perinatal lethal (also craniorachischisis)
Spina Bifida: caudal neuropore failure
- Occulta (unfused vertebral arches)
- Meningocoele
- Meningomyelocoele
- Myeloschisis aperta
Most common CNS malformation (was ~10/10,000 births, now ~2/10,000)
Multifactorial causes: a combination of genetic and environmental factors
What are the environmental factors associated with NTDs?
Maternal diet - Vitamin deficiency/malnutrition · Folate · Inositol - High levels of sugar Maternal obesity Diabetes Hyperthermia Teratogenic agents - Most prominently Valproic acid (VPA) which is an anti-epileptic drug A combination of these factors with genetic predisposition may lead to NTDs
How is folic acid associated with NTDs?
Clinical trials in humans in the 90’s showed a preventive effect of maternal folic acid supplementation prior to and during pregnancy
- 4mg folate; >5x ¯ recurrence risk; better with preconception start
Supplementation dose: 0.4mg/day or 5.0 for pregnant women
- Current practice: 0.4 general; 5 recurrence
Fortification better than supplementation?
- That was done so that as many women as possible had a lot of folic acid anyway
- e.g. mandatory cereal grain fortification in USA
- Fortification: ~ 70 - 200ug/day (USA, Canada)
- Log relationship between dose & protection
