Congenital diseases associated with central nervous system

Question 1

Name the structures that the neural tube (comes from folding of the neural plate) will differentiate into

Answer 1

brain
spinal cord
cranial and spinal nerves
eyes and other sensory organs
neural crest

Question 2

When does neurulation occur in humans?

Answer 2

Weeks 3 and 4

Question 3

Describe what gastrulation and neurulation is - there is a video linked here as a reminder of the week 2 embryology lecture!

Answer 3

“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. Neurulation is the formation of the neural tube

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. The following is a great video describing the changes in morphology that enable this transformation in a human embryo.”

Gastrulation is the formation of the 3 cell lineage

Question 4

Name the 3 cell lineages from gastrulation and what they each become

Answer 4

Ectoderm - becomes nervous system and skin

Mesoderm - (comes from ectoderm) becomes bones, connective tissue, peritoneal linings…

Endoderm - becomes lining of the internal organs

Question 4

What is the function of the notochord (reminder)?

Answer 4

Induces neurulation

Question 4

Looking from above, in what direction does neurulation advance?

Answer 4

Both cranially and caudally, starting from the middle

Question 5

Describe the process of neurulation

Answer 5

By the end of the 3rd week of development, the lateral edges of the ectoderm will become elevated = the neural fold, in the middle of the folds is the neural groove and the whole thing = neural plate as seen below. Looing from above, the closure of the tube will begin in the middle and advance in both directions (caudally and cranially).

Question 6

What is the neural crest?

Answer 6

As the neural tube forms, several neural tube cells migrate laterally to form the neural crest which gives rise to very many structures that are closely associated to the NS such as different ganglia

Question 7

What is meant by holoprosencephaly?

Answer 7

Is a defect of early patterning of the CNS

Question 8

Name some defects of neural tube closure

Answer 8

chraniorachischisis
excencephaly/anencephaly
spina bifida

Question 9

What is chraniorachischisis?

Answer 9

Complete opening (failure to close) the neural tube

Question 10

What is the difference between Spina bifida and anencephaly?

Answer 10

Anencephaly is when the anterior (rostral) end of the neural tube remains open

Spina bifida is when the posterior (caudal) end remains open

Question 11

How is neural tube closure different between humans and mice

Answer 11

Mice have 3 sites of closure whereas humans are thought to have the same 3 closure points + an additional 2 so 5 in total.

Question 12

Name where these closure points are in mice and humans

Answer 12

closure 1 = between hindbrain and spinal cord (starts first)
closure 2 = between midbrain and forebrain
closure 3 = between rostral forebrain (progresses only posteriorly)

Question 13

Which closure point can cause spina bifida in humans when defective?

Answer 13

closure 5 (progresses only anteriorly)

Question 14

Describe what primary vs secondary neurulation is

Answer 14

Primary neurulation is the rolling up and closure of the neural tube. Secondary neurulation is the tunnelling/hollowing of the tail bud - so this is only at the most caudal (posterior) region of the neural tube.

Question 15

In primary neurulation, explain how the neural plate is begins folding after the shaping of the plate

Answer 15

This is by the establishment of hinge points at various regions along the neural plate

Question 15

Name the first hinge point in neural tube folding

Answer 15

Midline hinge point (MHP) is the first one and runs along the midline of the neural plate

After this, convergence of the neural folds is done by other hinge points

Question 16

Name the mechanism used in the shaping of the neural plate (this is the step before neural plate folding)

Answer 16

convergence and extension

Question 17

Explain what cell wedging is

Answer 17

The bending of the neural tube at the hinge points involves cell wedging which is the remodelling of the microtubules and actin filaments

Question 17

Name the pathway that controls both the shaping of the neural plate and also cell wedging and so, therefore, the mechanism pivotal to primary neurulation

Answer 17

Wnt Planar Cell Polarity Pathway

Question 18

Describe how cells behave in convergence-extension (the mechanism used in neural plate shaping)

Answer 18

This is by ‘lengthening by narrowing’ which requires cells to become polarised and intercalate amongst each other

Question 19

How does neural plate shaping change the shape of it?

Answer 19

The tissue goes from broad and short to long and narrow

Question 20

Describe the Wnt-PCP pathway (ligand and receptor)

Answer 20

Wnt ligands (called Wnts) bind to frizzled (Wnt receptor). The human genome has 10 different frizzled receptors.

upon binding there is activation of Dishevel (Dvl) 1, 2 or 3
DVL 1, 2 and 3 will activate further mediators that have two effects: 1. to regulate transcription and 2. to regulate cytoskeleton

Question 21

What are Vangl and Celsr?

Answer 21

These are co-receptors necessary for signal transduction in the Wnt-PCP pathway (so they help the intracellular signal to be made from the fizzled)

Question 21

What is cell wedging, how does it happen?

Answer 21

This (alongside shaping of the neural plate as discussed above) is pivotal to effective primary neurulation and is also controlled by Wnt-PCP pathway. Is the change of the shape in the cell of the neural plate so that their apical side is very narrow causing them to act as a hinge so that the whole tissue folds - is driven by remodelling of the cytoskeleton at the apical surface of the cells

Question 21

Describe the shape of the neural tube and the defects when mutations are introduced in genes for celsr1, vangl, scribble, dvl1/2 and fzd3/6

Answer 21

In a mouse model, the neural plate is abnormally broad with a non-bending region between neural folds → causes chraniorachischisis this non-bending is due to the mechanisms involved in cell wedging (discussed below) mutations found in humans cause the same thing

Question 22

What exactly happens in cell wedging?

Answer 22

The actin filaments that run laterally across the surface of the cell are remodelled on the apical side so that it narrows. mechanism is the Wnt-PCP pathway as mentioned above

Question 22

Name some components of the maternal environment that are important to regulate in the first 3 weeks of pregnancy

Answer 22

Vitamin deficiencies (folate and insositol) Sugar (diabetes and obesity) Hypertemia (low body temperature) Teratogenic agents (valproic acid, teratogens halt the pregnancy or produce a congenital malformation (a birth defect). Classes of teratogens include radiation, maternal infections, chemicals, and drugs)

Question 23

Describe the relationship of serum phosphate level and incidence of NTD (neural tube defects)

Answer 23

linear relationship (with the inverse of NTD) very very high doses can have secondary effects and that is why you can’t just give huge amounts, despite the linear relationship

Question 24

Why wouldn’t we just give a very high dose of folate to everyone?

Answer 24

It is possible that it could cause B12 deficiency and therefore anaemia leading to neurotoxic complications or even promotion of colon polyps to cancer - both have not been confirmed. Folate also reduces palate and heart defects. Some NTDS can not be prevented by folate (around 30%)

Question 25

What is the involvement of inositol in the prevalence of neural tube defects (NTDs)?

Answer 25

Inositol has been shown to prevent NTDs in experimental models but there is insufficient evidence for humans yet

Question 26

What is meant by cell polarity, what controls it?

Answer 26

Controlled by the Wnt pathway I believe this is where intracellular components are different on either side of the cell