Reelin Mutations Flashcards
Lis1 mutation
Lis1 is a microtubule associated protein important for somal translocation. It interacts with motor proteins (centrosomes and dyenin)
- Mutation of Lis1 decouples the centrosome from the nucleus, thereby perturbing somal translocations.
Lis1 mutation causes type I lissencephaly: neurons fail to reach their correct location
Evidence for lis1 mutation
Neuronal migration assays in Lis1 mutants: Neurons usually migrate along lamins
Lis1 mutant don’t migrate using lamins and don’t extend along it
Cortical lamination is disrupted in lis1 mutants:
What causes meningeal breakdown?
- Pial membrane integrity depends upon the structure of the pia itself as well as appropriate contact with radial glial cells that interact with it.
Defects in the pial membrane or radial glia can lead to cobblestone cortex.
What is DCX?
Doublecortin (DCX) is a microtubule binding protein required for stabilising microtubules.
Why are related diseases are different in males and females.
X-linked inheritance patterns.
Affected males (one X chr) are homozygous carriers.
Affected females (two X chr) are heterozygous carriers
Cells expressing mutant DCX fail to migrate, giving rise to an additional band of cortical neurons in subcortical white matter.
What is lissencephaly and descrieb the two types?
Lissencephaly: “smooth brain”, deformation of ridges
Type I lissencephaly: gyri (ridges) and sulci (grooves)are lost in
Type 2: Cortex adopts bumpy appearance (cobblestone cortex) with too many small, fused gyri.
Describe Meningeal breakdown in type 2 lissencephaly
In normal brains the pial membrane ensheathes the cortical surface.
In cobblestone cortex, neurons migrate into marginal zone and then break through pial membrane, resulting in ectopic clusters of neurons lying outside the this region of the meninges.
Type 1: cells don’t migrate enough
Type 2: cells over-migrate
Evidence for interaction between plia membrane and dystroglycan
DiI injected into ventricular zone (labels radial glia fibers).
Co-stain with laminin (labels pial membrane).
In control, radial glia contact intact pial membrane.
In dystroglycan mutants, pial membrane breaks down. Radial glia often extend into meningeal space. Fibers also become disorganised.
Describe interactions between plia and radial glia
Interactions between pial membrane and radial glia processes are important for integrity of preventing over-migration.
These interactions are mediated by extracellular matrix components on pial membrane that binding to receptors expressed on radial glia endfeet.
One critical interaction is mediated through the ECM component laminin and the dystrophin glycoprotein receptor complex.
- Beta-dystroglycan is expressed at the pial surface of the developing cortex.
End feet of radial glia cells interact with dystroglycan rich region at top
Evidence for mutationof fukutin and lissencephaly
- The pial membrane breaks down in Fukutin chimera’s.
- No protective layer between radial glia and arachnoid space
Radial glia orientation and number appear normal during early neurogenesis but these cells lose contact with pial membrane as it disintegrates.
Although role of Fukutin is not clear, it is likely to be important for glycosylation of dystroglycan (as with POMGnT1).
Mutations of FOXC1 and radial glia
FOXC1 is a transcription factor.
Important for formation of pial membrane (exact function not yet clear).
FOXC1 mutants lack this protein in developing pia
The basal lamina breaks down in FOXC1 mutants. Pial membrane starts to fall apart.
As pia breaks down, radial glia lose contact with meninges.
As a consequence, radial glia processes become disorganised.
Evidence that cobblestone cortex is not due t neuronal overproduction
POMGnT1 gene is neccesary for normal integrin-dysteroglycan interactions.
Participates in glycosylation of dystroglycan
Mutated in muscle-eye-brain disease.
POMGnT1 mutants exhibit improper lamination of layer 5 neurons and cell bodies that have over-migrated beyond this layer.
This suggests phenotype is not due to over-production of neurons.
