Congenital Disease Associated with Central Nervous system Flashcards
What is Neurulation and at what stage will it occur ?
Neurulation = the process of neural tube formation, occurs at around week 3/4
What does the neural tube form ?
The brain, spinal cord, meninges (membranous covering of brain and spinal cord) and bones that surround them.
cranial nerves, spinal nerves, neural crest, eyes, other sensory organs
What are the three layers of the embryo ?
3 primary germ layers:
Ectoderm
Mesoderm
Endoderm
What is Gastrulation?
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.
Gastrulation = the 3 primary germ layers form + start becoming diff. tissue types
occurs in week 3 of development
What does the Ectoderm differentiate into?
This will form the outer component’s of the body e.g.:
Skin
Hair
Nervous system
Mammary glands
What does the Mesoderm differentiate into ?
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
What does the Endoderm differentiate into ?
The pharynx
Oesophagus
Stomach
Small intestine
Colon
Liver
Pancreas
Bladder
Trachea
Bronchi
Lungs
Thyroid
Parathyroid
lines GIT + airways
What is the notochord
The Notochord induces neurulation and will later form the nucleus pulposus
(soft gelatinous central portion of the intervertebral disk )
What is the somite ?
Somites 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.
Describe process of Neurulation
By the end of week3 :
The lateral edges of the ectoderm will become more elevated and form the neural fold.
The depressed mid region = the neural groove. The whole layer = the neural plate (of the ectoderm).
Neurulation will advance both cranially (brain/head) and caudally (tail/spinal chord). It starts from mid-region.
The neural plate will form neural folds on either end, forming the depression in the middle = the neural groove.
How does the neural tube form ?
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.
Describe how the neural crest will form and what’s the function of this structure ?
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 nerves, cranial nerves, ganglia
Autonomic nervous system ganglia
Meninges
What are the different sections of the neural tubes ?
- Prosencephalon - Cerebrum and thalamus
- Mesencephalon - Mid brain
- Rhombencephalon - Pons cerebellum and medulla
- Spinal chord - Spine
What is an Anencephaly
Anencephaly:
Birth defect in which a baby is born without parts of the brain / skull.
Neural tube defect.
Opening is in anterior region
What is Craniorachischisis?
Neural tube defect - neural tube fails to close
Entire spinal cord and brain are exposed.
What is spina bifida ?
Spina bifida:
A birth defect (NTD) that occurs when the spine and spinal cord do not form properly
Opening at the caudal region of neural tube
Where does the closure of the neural tube begin?
(In a mouse)
This occurs at three different locations:
Closure 1 (Craniorachischisis) -Located at the edge between hind brain and spinal chord, progresses anteriorly+posteriorly
Closure 2 (Anencephaly) -Edge between forebrain and mid brain, progresses anteriorly + posteriorly
Closure 3 (Spina bifida) -Most rostral portion of forebrain-progresses posteriorly
What are the additional closures found in humans and where are they located ?
Closure 4
More rostrally within hindbrain than closure 1
Closure 5
Very posterior portion of the neural plate and progresses anteriorly.
see ‘closure of the cranial and caudal neuropores slide’ - https://sgul.cloud.panopto.eu/Panopto/Pages/Viewer.aspx?id=93c0cd92-dd97-4221-b1d4-ad4e009ff7d9&start=0
What are the two modes of neural tube closure?
Primary Neurulation:
- Rolling up of the tube, neural plate folds to give rise to neural tube
- Closure is by fold apposition then “zipping up”
- Is completed when it reaches the Cranial and Caudal neuropores
Secondary Neurulation:
- Tunnelling or hollowing of tail bud
- Forms caudal-most tip of neural tube
The primary and secondary neural tubes fuse + become continuous at Somites 30-31 in human (2nd sacral region)
What is a neuropore ?
Neuropore = Open regions of the neural tube.
Caudal Neuropore:
temporary opening at the extreme caudal end of the neural tube in the early embryo
Cranial Neuropore:
temporary opening at the extreme rostral (cephalic) end of the neural tube in the early embryo
What are the steps of primary neurulation?
- Shaping
It is originally broad in mediolateral axis and short along rostrocaudal axis. It will narrow down along mediolateral axis + become longer along the rostral caudal axis.
First step, essential for neurulation - 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 of neural plate become closer to each other along midline
4.Convergence
The neural folds/edges become further opposed to each other. More hinge points and more dorsal regions form as neural plate folds.
- Closure
The two folds fuse, leading to complete closure of neural tube
What are the 2 main processes which are essential to the folding of the neural plate into neural tube ?
- Shaping of the neural plate occurs by convergence/extension
Tubing (Formation of the tube) requires bending at hinge points
- Cell wedging at hinge points - Microtubules and actin filaments are remodelled - The process through which hinge points are created.
Both processes are controlled by Wnt-PCP pathway
How are the two processes (convergence/extension + cell wedging) controlled?
The Planar Cell Polarity pathway
What is the process of convergence and extension?
This is the process of lengthening by narrowing the tissue, 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 elongates as we still have the same number of cells within the tissue. tissue elongates in anterior-posterior axis. broad, short tissue → long, narrow tissue. this happens during the shaping of the neural plate
Outline the components within the Wnt-PCP pathway
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.
Outline the Wnt-PCP pathway
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 cellular response. This response requires the activity of transmembrane proteins - Celsr1 and Vangl.
The first molecule which is targeted after Wnt-Frizzled binding is Dvl1-3.
DVl1-3 aids transcription regulation + regulation of the dynamics of the cell’s cytoskeleton.
Wnt-PCP pathway is important for the shaping of the neural plate. Mutant = Defect = neural plate doesn’t shape appropriately = remains abnormally broad + absence of bending regions b/w neural folds
What mouse mutants show neural tube defects ?
Mouse mutants in the Wnt-PCP pathway cause craniorachischisis (neural tube defect)
Defects in:
Celsr1-/- (crash)
Vangl-/- (loop tail)
Scribble -/-(circle tail)
dvl1/2
fzd3/6
In mutants, the neural plate is abnormally broad with a non-bending region between neural folds which leads to craniorachischisis (neural tube fails to close)
What is cell wedging and apical constriction ?
Cell wedging and apical constriction:
This is the mechanism by which the hinge points are formed.
There is a change in the shape of the cells of the neural plate, causing the apical side to become very narrow. The bottle shape makes it work as a hinge - the tissue moves along this region. This process (apical constriction of the cells) is driven by the remodelling of the cytoskeleton at the apical cortex of the cell.
Describe the changes which occur within epithelium cells
Cells in an epithelium have apico-basal polarity. The cells are polarised along the apico-basal axis (basal region + apical region of epithelium).
The cytoskeleton is polarised within the cell and at the sub-apical region of cell, there are tight arrays of actin filaments which are important to maintain the shape of the cells. These arrays of actin filaments 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 - controls actomyosin cytoskeleton at the apical side of the cell so it contracts along mediolateral axis = epithelium changes shape + hinge points form
What are some environmental factors which are associated with NTDs?
- Maternal diet
- Vitamin deficiency/Malnutrition - Folate, Inositol
- High levels of sugar
- Maternal obesity
- Diabetes
- Hyperthermia = severe disease with high fever
- Teratogenic agents (Valproic acid = antiepileptic drug)
What is the relationship between folic acids and NTDs?
Women with low folic acid levels = more likely to have pregnancy with Neural Tube Defect
Clinical trials in humans in 1990s showed a preventative effect of maternal folic acid supplementation prior to + during pregnancy.
This reduced recurrence risk of NTD in the pregnancy.
We now supplement folic acid for women planning pregnancies:
0.4mg/day for no previous history of pregnancy with NTD
5mg/day for previous history of pregnancy with NTD
Only supplementing with folic acid provides less reduction risk for NTDs than …………..
supplementation + fortification of foods with folic acid
What are some potential problems with folic acid ?
What other defects does folic acid supplementation prevent?
Does folic acid supplementation prevent all NTDs?
B12 deficiency - reduces detection by masking anaemia, allows neurotoxic complications
Promotion of colon polyps to cancer
Reduces palate defects
Reduces heart defects
There are still some NTDS which cannot by prevented by folate = folate resistant NTDs.
- Supplement with inositol to prevent NTDs.
What is being tested as an alternative to folic acid ?
Inositol
Can prevent NTDS in experimental models
Neurulation starts in ……… and advances ……………
mid-region
both cranially and caudally
gradual subdivision of the neural tube along the rostro-caudal axis
see canvas pg diagram - https://canvas.sgul.ac.uk/courses/3095/pages/congenital-diseases-associated-with-central-nervous-system-sdl?module_item_id=139628
Congenital defects can arise from perturbation of different steps during CNS formation. In the document below, you will find a brief classification of defects according to the stage that is thought to be affected, including the following:
- Defects of early patterning of the CNS: holoprosencephaly
- Defects of neural tube closure: chraniorachischisis, exencephaly/anencephaly, spina bifida.
- Regional brain defects: rostro-caudal defects.
file:///C:/Users/xavia/Dropbox/My%20PC%20(DESKTOP-GJINL6L)/Downloads/NTDs.pdf
What happens at the hinge points?
Hinge points are where the neural plate folds
The mutants in mouse embryos affecting the Wnt-PCP signalling pathway cause defects in the shaping of the neural plate, and also lack which process?
Mediolateral contraction of apical cytoskeleton that forms the hinge points
Shaping of neural plate occurs by ………
Tubing requires ………..
Cell wedging occurs at ………
Defective convergence/extension and cell wedging =
convergence/extension
bending at hinge points
hinge points - microtubules + actin cytoskeleton apical constriction
craniorachischisis = neural plate fails to close to form the neural tube
