Congenital Disease Associated with Central Nervous system

Question 1

What is Neurulation and at what stage will it occur ?

Answer 1

This is the process through which the neural tube forms and this occurs at around week 3/4

Question 2

What does the neural tube form ?

Answer 2

The brain, spinal chord ,meninges ( membranous covering of brain and spinal chord ) and bones that surround them.

Question 3

What are the three layers of the embryo ?

Answer 3

Ectoderm
Mesoderm
Endoderm

Question 4

What is Gastrulation?

Answer 4

Gastrulation is the process during embryonic development that changes the embryo from a blastula with a single layer of cells to a gastrula containing multiple layers of cells.

Question 5

What does the Ectoderm differentiate into?

Answer 5

This will form the outer component's of the body such as :
Skin
Hair 
Nervous system
Mammary glands

Question 6

What does the Mesoderm differentiate into ?

Answer 6

This will give rise to :
skeletal muscles
smooth muscle 
blood vessels 
bone 
cartilage 
joints 
connective tissue 
endocrine glands
Kidney cortex
Heart muscle 
urogenital organ 
uterus 
fallopian tube

Question 7

What does the Endoderm differentiate into ?

Answer 7

The pharynx
Oesophagus
stomach 
Small intestine 
Colon
Liver 
Pancreas
Bladder
Trachea
bronchi 
lungs
Thyroid 
Parathyroid

Question 8

What is the notochord

Answer 8

This induces neurulation and will then form the nucleus pulposus
(soft gelatinous central portion of the intervertebral disk )

Question 9

What is the somite ?

Answer 9

These are a set of bilaterally paired blocks of paraxial mesoderm that form the vertebrae, ribs and dermis of the dorsal skin, skeletal muscles of the back and the skeletal muscles of the body wall and limbs.

Question 10

Describe process of Neuralation

Answer 10

By the end of week3 :

The lateral edges of the ectoderm will become more elevated and form the neural fold.
The depressed mid region is called the neural groove. The whole layer is referred to as the neural plate.

Neurulation will advance both cranially (brain /head) and caudally (Tail/ spinal chord)

The neural plate will form neural folds on either end forming the depression in the middle =the neural groove.

Question 11

How does the neural tube form ?

Answer 11

The outer parts of the neural fold will fuse together forming the neural tube.

The outer section of the ectoderm will move and surround the endoderm and mesoderm.

Question 12

Describe how the neural crest will form and what’s the function of this structure ?

Answer 12

Week 4

Some of the ectodermal cells will migrate forming several layers of cells called the neural crest.

This will give rise to structures that work closely with the nervous system

E.g- Peripheral nervous system spinal and cranial nerves +ganglia

Autonomic nervous system ganglia
Meninges

Question 13

What are the different sections of the neural tubes ?

Answer 13

Prosencephalon-Cerebrum and thalamus
Mesencephalon -Mid brain
Rhombencephalon -Pons cerebellum and medulla
Spinal chord -Spine

Question 14

What is an Anencephaly

Answer 14

Birth defect in which a baby is born without parts of the brain / skull.
Neural tube defect.
Opening is in anterior region

Question 15

What is Craniorachischisis?

Answer 15

Occurs when the entire spinal chord and brain are exposed.

Question 16

What is spina bifida ?

Answer 16

This is a birth defect that occurs when the spine and spinal chord do not form properly

This is in the caudal region .

Question 17

Where does the closure of the neural tube begin?

In a mouse

Answer 17

This occurs at three different locations :
Closure 1-Craniorachischisis
(Located at the edge between hind brain and spinal chord)

Closure 2 -Anencephaly
(Edge between forebrain and mid brain )

Closure 3-Spina bifida
(Most rostral portion of forebrain-progresses posteriorly)

Question 18

What are the additional closures found in humans and where are they located ?

Answer 18

Closure 4
More rosterly in hindbrain than closure 1

Closure 5
Very posterior portion of the neural plate and progresses anteriorly.

Question 19

What are the two modes of neural tube closure?

Answer 19

Primary Neurulation -
Rolling up of the tube
Closure is by fold apposition then “zipping up”
Cranial and caudal neuropores

Secondary neurulation
Tunnelling or hollowing of tail bud

The primary and secondary neural tube becomes continuous
Region of fusion
Somities 30-31 in human (2nd sacral)

Question 20

What is a neuropore ?

Answer 20

Caudal Neuropore
temporary opening at the extreme caudal end of the neural tube in early embryos

Cranial Neuropore
temporary opening at the extreme rostral (cephalic) end of the early embryonic

Question 21

What are the steps of primary neurulation?

Answer 21

1.Shaping
It is originally broad in medial lateral axis and short along rostral caudal xis.It will narrow dbecome longer along the rostral caudal axis.
The first step is essential for neurulation

2.Folding
There are hinge points established. The first is the midline hinge point along the middle of neural plate.

3.Elevation
The folding of the lateral wings of neural plate.The edges become closer to each other along mid line

4.Convergence
The neural folds become further opposed to each other. There are more hinge points and more doral regions.

The two folds fuse and leads to a complete closure of neural tube

Question 22

What are the two main processes which are essential to the folding of the neural plate into neural tube ?

Answer 22

1. Shaping of the neural plate occurs by convergence/extensions

Tubing requires bending at hinge points

2. Cell wedging at hinge points-Microtubules and actin filaments are remodelled -The process through which hinge points are created.

Question 23

How are the two processes controlled

Answer 23

The Planar Cell polarity pathway

Question 24

What is the process of convergence and extension?

Answer 24

This is the process of lengthening by narrowing which requires cells to become polarised in the plane of the cell layer.

The cells will intercalate within each other. Changing the shape of the cells. This leads to narrowing of the tissue. The tissue will elongate as we still require the same number of cells within the tissue.

Question 25

Outline the components within the Wnt-PCP pathway

Answer 25

Wnts: secreted signalling molecules -the ligand ,these will bind to receptors

Frizzleds:Wnt receptor transmembrane proteins
There are 10 different types encoded in human genome.

Vangl and Celsr: Co-receptors necessary for signal transduction

Dvl1-3: Cytoplasmic proteins, activated upon interaction between Wnts and Fzds.

Question 26

Outline the Wnt-PCP pathway

Answer 26

The Wnts will bind to the Frizzleds which are found on the cell membrane. Once bound, the frizzled will undergo a conformational change triggering a response. This requires the activity of Celsr 1 and Vangl proteins which are transmembrane proteins.
The first molecule which is targeted is Dvl1-3.

DVl1-3 leads to the regulation of transcription and the regulation of the dynamics of the cells cytoskeleton.

Question 27

What mouse mutants show neural tube defects ?

Answer 27

Mouse mutants in the Wnt-PCP pathway cause craniorachischisis.

Celsr1-/- (crash)
Vangl-/- (loop tail)
Scribble -/-(circle tail)
dvl1/2
fzd3/6

The neural plate is abnormally broad with a non- bending region between neural folds which leads to craniorachischisis.

Question 28

What is cell wedging and apical constriction ?

Answer 28

This is the mechanism by which the hinge points are being formed. There is a change in the shape of the cells in the neural plate. This causes the apical side to become very narrow. The bottle shape makes it work as a hinge.
This process is driven by the remodelling of the cytoskeleton at the apical section of the cell.

Question 29

Describe the changes which occur within epithelium cells

Answer 29

The cells in an epithelium have apico-basal polarity. The cells are polarised within the apico- basal axis. The cytoskeleton is polarised and at the sub-apical region , there are tight arrays of actin filaments which are important to maintain the shape of the cells. These are the filaments which are remodelled to make the cell bottle shape. It becomes contracted along the medial -lateral axis

This process of narrowing the apical side of the cell is driven by the WNT-PCP pathway.

Question 30

What are some environmental factors which are associated with NTDS.

Answer 30

Maternal diet
-Vitamin deficiency/Malnutrition
(Folate, inositol)
-High levels of sugar

Maternal obesity 
Diabetes
Hypertermia 
Teratogenic agents 
-Valproic acid

Question 31

What is the relationship between folic acids and NTDS ?

Answer 31

Clinical trials in humans in the 90s showed a preventative effect of maternal folic acid supplementation prior to and during pregnancy.

There was a reduction of recurrence risk

Question 32

What are some potential problems with folic acid ?

Answer 32

B12 deficiency -reduces detection by masking anaemia)
Promotion of colon polyps to cancer
Reduces palate
Heart defects

There are still some NTDS which cannot by prevented by folate -folate resistant NTD

Question 33

What is being tested as an alternative to folic acid ?

Answer 33

Inositol

Can prevent NTDS in experimental models