Lecture 4

1. Describe the three types of neurulation discussed in class (primary, secondary, junctional)

- Primary - formation of neural tube from neural plate

- ectoderm thickens to form neural plate

- edges of plate rise up creating neural folds, center sinks down forming neural groove. folds meet in middle to form tube

- Secondary - condensation and canalization

- at tail bud condensation of cells forms medullary cord, cells in the center move to edges to form a tube

- Junctional - merges the primary and secondary neural tube

- top half of junctional region undergoes primary neurulation, cells in neural groove form connection to medullary cord

2. What process creates the primary and secondary neural tubes?

- primary neurulation rolls up sheet into a tube, secondary neurulation is condensation and canalization

3. Describe these neural tube defects discussed in class

- exencephaly/anencephaly

- failure to close neural tube at points 2/3 at rostral end (exencephaly)

- exposed neural tissue of top of head is degraded (anencephaly)

- no survival / results in miscarriage

- craniorachischisis

- failure to initiate closure at point 1 (cervical-hindbrain boundary)

- exposed neural tissue along back, sometimes head

- no survival / results in miscarriage

- spina bifida / myelomeningocele

- localized area where neural tube did not close, or opening formed to surface during secondary neurulation

- fluid filled sac at site of lesion

- defect in vertebrates in area

- tethered cord

- adhesions between conus medullaris (end of spinal cord) and surrounding bones or tissues

- prevent vertebrates from moving as child grows → stretches nerves

- can be surgically repaired

1. What are the challenges and life expectancy of individuals with myelomeningocele?

- reduced life expectancy

- neurological (motor and sensory) problems

- orthopedic problems

- lack of bladder control

- Arnold Chiari II malformation in brain → hydrocephalus

2. What is the Arnold Chiari II malformation and how is it related to myelomeningocele?

- low lying forth ventricle with displaced cerebellum

- caused by leaking of cerebrospinal fluid out of myelomeningocele during development

- improper maintenance of hydrostatic pressure in CNS

3. What is the two-hit hypothesis for neurological disability in myelomeningocele?

- first hit - failure to close - neurons can’t develop

- second - neurodegeneration over time on either side of myelomeningocele due to exposure to neurotoxic substance in amniotic fluid

4. What were the finds of the MOMS trial?

- in utero repair was more effective at obtaining independent walking and preventing Arnold Chiari malformation

- side effects → weaking of uterus

5. What is the difference between a complex trait and a mendelian trait?

- complex: determined by combined effect of multiple genetic variants of low or intermediate impact, plus strong environmental component

- Mendelian: determined by high impact genetic variants in single gene

6. Describe the role of dietary folate in the etiology and prevention of neural tube defects?

- Folate supplementation decrease incidence of NTDs

- poor diet lacking folate identified as an environmental factor that predisposes individuals to NTD

- must be obtained through diet

7. What are the purposes of the folate cycle and the methionine cycle?

- Folate cycle produces purines

- Methionine cycle produces SAM (universal methyl donor )

- Both are critical for DNA replication, RNA transcription, DNA and protein methylation

- determines which genes will be expressed or silenced

8. What methods have been used to prevent neural tube defects at the population level?

- Educational efforts to encourage people to take folate supplements

- Mail free folic acid vitamins

- Supplement food supply by adding folate to staple item (e.g. flour)