Congenital Diseases Associated with Central Nervous System Flashcards
Explain the steps of morphogenesis
- Fusing of neural folds
- fusing starts between hindbrain and spinal cord and progresses up and down
What are the possible deformities of neural tube closure
- Anencephaly (more cranial)
- Cranioarchischisis
- Spina bifida (more caudal)
Where are the closure points in mouse
Closure 1 - Between the hindbrain and spinal cord
Closure 2 - On top of the head
Closure 3 - Near the face
Where are the closure points in human
Closure 1 - Between the hindbrain and spinal cord
Closure 2 - On top of the head
Closure 3 - Near the face
Closure 4 - Just above number 1
Closure 5 - Most caudal end
What are the 2 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:
tunnelling or hollowing of tail bud
The primary and secondary neural tube become continuous
Somites 30-31 in human (2nd sacral)
What are the steps in primary neuralation
Shaping of the neural plate occurs by convergence/extension
Tubing requires bending at hinge points
Cell wedging at hinge points: microtubules & actin filaments
Describe 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 the Wnt-PCP pathway
It is a network of proteins that lead to changes in the transcriptional state of the cell
What are the steps in the Wnt-PCP signalling 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
What mutations in the Ant-PCP pathway can lead to neural tube defects
Mouse mutants in components of the Wnt-PCP pathway show neural tube defects:
celsr1-/- (crash)
vangl-/- (loop-tail)
scribble-/- (circletail)
dvl1/2
fzd3/6
The neural plate is abnormally broad with a non-bending region between neural folds - leading to chraniorachischisis
Describe how cell wedging and apical constriction occurs
Actin myosin filament in the cell contract at the apical portion contracting the cell to a bottle shape.
The cytoskeleton is polarised and the actin-myosin filament the maintain the shape
how does mutation lead to lack of neural tube closure
celsr1-/- (crash)
vangl-/- (loop-tail)
scribble-/- (circletail)
dvl1/2
fzd3/6
- these messengers mediate the constriction an when mutated it doesn’t take place
- therefore neural tube closure doesn’t occur
what are the Environmental factors associated with NTDs
- Maternal diet
Vitamin deficiency/malnutrition
Folate
Inositol
High levels of sugar - Maternal obesity
- Diabetes
- Hypertermia
- Teratogenic agents
Valproic acid (VPA) - Alcohol
How is folic acid important in 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:
Current practice: 0.4 mg/day general; 5 mg/day recurrence
…but supplementation does not reach everyone - Fortification better than supplementation?
e.g. mandatory cereal grain fortification in USA
Fortification: ~ 70 - 200ug/day (USA, Canada)
What are the uses of Folic acid
- Nucleotide synthesis
- Serine-glycine interconversion
- Mitochondrial tRNA modification
- Methyl group biogenesis
proliferation
respiration
epigenetic modifications
