Congenital diseases associated with CNS Flashcards
What is the first step in the formation of the central nervous system?
= formation of the neural plate, and its folding to give rise to the neural tube. The neural tube will then differentiate into the following structures:
- the brain
- the spinal cord
- the cranial and spinal nerves
- the eyes and other sensory organs
- the neural crest
How does the neural plate transform into 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.
What happens when the neural tube closes?
it becomes patterned along the dorso-ventral and the rostro-caudal axes.
This process is driven by secreted signalling molecules, which promote the specification of different CNS structures along each axis.
What are the 3 germ layers in the embryo?
Ectoderm –> give rise to nervous system and skin
Mesoderm –> form the connective tissue and bone, muscle
Endoderm –> lining of internal organs
- Notochord induces neurulation and later will form the nucleus pulposus of intervertebral
What are the congential defects that can arise from CNS formation?
Defects of early patterning of the CNS
- Holoprosencephaly
- structual malformation of the forebrain
- mutation in the SHH which leads to mis-specificatoin of the future ventral regions of the forebrain
Defects of the neural tube closure
- Craniorachischisis
- Exencephaly/anencephaly - lack of closure results in ‘brain exposured’ or ‘lack of brain’ (respectively)
- Spina bifida - malformation of the spine/spinal cord due to failure of closing of neural tube
Regional Brain defects
- restro-caudal defects
What are the 2 modes of neural tube closure?
Primary neurulation
- rolling up of tube, closure is a fold then zipping up
- occurs by convergence/extension
- tubing requires bending at hinge points
- cell wedging at hinge points are controlled by planar cell polarity pathway
Secondary neurulation
- tunnelling or hollowing of tail bud
Primary and secondary become continuous
What is the process of convergence and extension?
What is the planar cell polarity pathway?
- The signal that the cell receives is coming in the form of molecules = Wnts
- They bind to a receptor in the membrane of the cell = Frizzleds
- Free cell will undergo a confirmational change that will trigger a response within the cell (requiring activity of several other molecules eg. Vangl and Celsr)
- Within the cell, the first molecule that becomes targeted by the activation of these membrane complex is Dvl (3 types) (activated upon interaction with Wnts and Frizzleds)
- Downstream, Dvl with other proteins lead to the regulation of transcription and regulation of cytoskeleton
What are the different proteins involved in the planar cell polarity pathway?
Network of proteins that will lead to changes in their behaviour or their transcription
- Wnts: secreted signalling molecules – the ligand
- Frizzleds: Wnt receptor, transmembrane proteins
- Vangl and Celsr: co-receptors necessary for signal transduction
- Dvl1-3: cytoplasmic proteins, activated upon interaction between Wnts and Fzds
How has the planar cell polarity pathway been studied in many model organisms?
They have used different mouse mutants in components of the Wnt-PCP pathway to show neural tube defects:
- Celsr1 (crash)
- Vangl (loop-tail)
- Scribble (circletail)
- Dvl 1/2
- Frizzleds 3/6
**In all these cases, the neural plate is abnormally broad with a non-bending region between the neural folds leading to chranioschischisis**
The same genes have been found mutated in human patients that have chranioschischisis or other defects of the neural tube:
What is cell wedging?
Mechanisms by which the hinge points (where the neural plate folds) are being formed
Involving change of shape of the cells in neural plate to become narrow apical constriction
- Apical constriction is driven by the remodelling of cells of cytoskeleton at the apical cortex
Therefore the hinge forms as the tissue comes together
What are the cellular and molecular mechanisms of primary neurulation?
- Shaping of the neural plate occurs by convergence/extension
- Tubing requires bending at hinge points
- Cell wedging at hinge points: microtubules and actin filaments
- Defective convergence/extension and cell wedging leads to chraniorachischisis
What are the environmental factors associated to neural tube defects?
Maternal diet (due to how early the neural plate folding occurs so women may not yet know they are pregnant)
- Vitamin deficiency/malnutrition
- High levels of sugar
Maternal obesity
Diabetes
Hyperthermia
Teratogenic agents - valproic acid
What is the link between folic acid and nerual tube defects?
Women with low levels of folic acid have more risk of NTDs in their babies.
Folic acid supplementation was reducing the risk of NTDs
What is the significance of the cells epithelium having a apico-basal polarity?
The polarity creates a barrier that allows for selective vectoral transport of macromolecules for absorption or secretion
Actin filaments are remodelled as the cell changes shape and folds
- Becomes contracted along the media-lateral axis which leads to change of the shape of epithelium and formation of hinge points
