6- Congenital Diseases associated with CNS

Question 1

what is neurulation?

Answer 1

occurs during week 4 of embryogenesis - specialised neural plate becomes a closed neural tube in a developing embryo

Question 2

what are the 5 closure points for neural tube closure in humans?

Answer 2

1st - at the edge between the hindbrain and spinal cord

2nd - edge between the forebrain and midbrain

3rd - most anterior/head position of forebrain

4th - within the hindbrain, more rostral/ towards head than 1st

5th - very posterior portion of the neural tube

Question 3

what neural tube defect will failure of closure point 1 cause?

Answer 3

craniorachischises - brain and spinal cord remain open

Question 4

what neural tube defect will failure of closure point 2 cause?

Answer 4

anencephaly - absence of a major portion of the brain, skull, and scalp

Question 5

what neural tube defect will failure of closure point 3 cause?

Answer 5

spina bifida - improper development of baby’s spinal cord causing a gap in the spine

Question 6

what are the two stages of neurulation?

Answer 6

primary neurulation - process by which the neural tube is shaped from the neural plate; precursor for the brain and spinal cord

secondary neurulation - process by which the caudal/ tail end of the neural tubes forms by hollowing out the interior of the precursor; development of spinal cord continues beyond mid-thoracic level

Question 7

what are the two key processes in primary neurulation?

Answer 7

1. shaping the neural plate by convergence and extension
2. formation of hinge points through cell wedging

Question 8

describe the process of shaping the neural plate

Answer 8

before shaping - neural plate is wide along the medial-lateral axis and short along the rostral-caudal/ anterior-posterior axis
- neural plate is narrowed/ converges along ML axis and extends along RC axis = ensures more efficient neurulation

this process of convergence and extension involves cells becoming polarised and intercalating - lateral cells move to intercalate with medial cells

Question 9

describe the process of forming hinge points

Answer 9

first hinge point forms at the midline of the neural plate - cells along this hinge point are MHP/ medial hinge point cells

lateral edges fold, converge around midline line, keep folding until both neural folds appose each other

more hinge points form along neural plate - apposing neural folds fuse to form a closed neural tube

Question 10

what is cell wedging? why is it important in forming hinge points?

Answer 10

cell wedging - occurs when the Wnt-PCP signalling pathway induces changes in cell shape by cytoskeleton/ actomyosin filament & microtubule rearrangements, especially at the apical side of cells
- causes constriction of apical side of cells = become bottle-shaped and narrow = allows them to work as hinge points during neural plate folding

importance:
- without cell wedging = no apical constriction = neural plate ends up abnormally broad with non-bending/ non-hinge regions
= no initial bending regions for neural plate folds = neural tube can’t form
= causes craniorachischises

Question 11

what is the Wnt-PCP signalling pathway?

Answer 11

occurs in medial cells of the neural plate - induces changes in cell cytoskeleton & microtubule arrangement, and transcriptional activity

important for apical constriction of medial neural plate cells, for the formation of hinge points for neural plate folding

Question 12

what are the components for Wnt-PCP signalling pathway - describe each?

Answer 12

Wnt = secreted signalling molecule

Frizzleds = transmembrane receptor - over 10 genes encode different Frizzleds, which are activated by different combinations of Wnt signalling molecules

Celsr + Vangl = transmembrane co-receptors for intracellular signal transduction

Dvl 1-3 proteins = cytoplasmic proteins activated upon Wnt-Frizzleds interaction

Scribble + Diversin = downstream proteins of the Wnt-PCP transduction pathway

Question 13

what secretes Wnt?

Answer 13

dorsal mesoderm

Question 14

what is the name of the Wnt receptor?

Answer 14

Frizzleds

Question 15

describe the Wnt-PCP signalling pathway, and how it contributes to primary neurulation

Answer 15

mechanism:
Wnt is secreted by dorsal mesoderm and binds to Frizzleds receptor on neural plate cells

induces a conformational change in Frizzleds = triggers cell response

Celsr and Vangl transduce the signal with Frizzleds - target Dvl 1-3 proteins first = signal interacts with further downstream proteins like Scribble and Diversin

downstream proteins exert effects:
- regulate cell cytoskeleton dynamics through actomyosin filaments which maintain cell shape and microtubules
- regulate transcriptional activity of cell

importance:
mutations in components of Wnt-PCP signalling pathway develop craniorachischises - fail apical constriction, fail to form hinge points, fail to form neural tube

Question 16

what factors are important in the formation of hinge points?

Answer 16

shaping of the neural tube through convergence and extension - mediolateral contraction and rostral-caudal extension is important for efficient neurulation

cell wedging - constriction of the apical side of cells along the neural plate midline/ MHP cells = allows them to function as hinge points

Wnt-PCP pathway components and signal transduction - no mutations, no interfering with signal transduction
= allows for rearrangement of cell cytoskeleton and microtubule and actin-myosin filament dynamics
= allows for changes in apical side of cells to become narrower and more bottle-shaped

Question 17

what are the three main NTDs in humans? what causes them?

Answer 17

1. craniorachischises
   - failure of closure 1; the first closure point, closure progresses anteriorly and posteriorly
   - closure 1 defects affect the whole neural tube
   - mutations in Wnt-PCP pathway components
   - improper formation of hinge points/ cell remodelling/ cell wedging
   - improper convergence and extension/ shaping of neural plate
2. anencephaly = failure of closure 2/ cranial neuropore
   - anterior portion of neural tube remains open, neural tissue of brain is exposed
3. spinal bifida = failure of closure 3/ caudal neuropore
   - defects in spine and spinal cord development = causes gap in spine

Question 18

list environmental factors associated with NTDs

Answer 18

• maternal diet = vitamin deficiencies in folate or inositol, high sugar
• maternal obesity or diabetes
• hyperthermia
• teratogenic agents - e.g. alcohol, valproic acid (treats migraines and epilepsy)

NTDs cause by a combination of environmental factors and genetic predisposition

Question 19

describe the relationship between folic acid and NTDs in babies

Answer 19

strong relationship between folate deficiency and NTDs in babies - folic acid supplementation has a preventative effect in approx. 70% of cases

mutations in folate related genes - e.g. FOLR1, transporters and enzymes in folate metabolism - are associated with NTDs
- high expression of FOLR1 in neural tube = folate needed for tube course

often predisposing mutation + folate deficiency = NTD development

Question 20

effects of folate on cells?

Answer 20

• nucleotide synthesis
• methyl group biogenesis = affects proliferation, respiration and epigenetic modifications
• mitochondrial RNA modification

widespread distribution and effects in all somatic cells

Question 21

transport of folate in cells?

Answer 21

folate binds to FOLR receptor on cell membrane - taken into cell by endocytosis

special transporters take folate across cellular membranes to exert its effects - e.g. nucleotide synthesis, mitochondrial RNA synthesis, methyl group biosynthesis…

Question 22

describe the relationship between inositol and NTDs in babies

Answer 22

approx. 30% of NTDs can’t be prevented despite folate supplementation - inositol is a possible alternative

inositol supplementation can reduce frequency of spina bifida - may modulate cell proliferation, polarity and motility which contributes to proper neural tube development

BUT there’s insufficient evidence for this

Question 23

what are the functions of inositol?

Answer 23

synthesis of PIP (phosphoinositides) molecules - e.g. PIP2, 3 - which are:
- structural components for plasma membranes
- mediators in signalling pathways for important cellular processes

involved in glucose metabolism and insulin regulation - regulates BGL, involved in insulin signalling pathways

adequate inositol levels needed for proper neural tube formation