Week 4 Flashcards
Where does the cerebellum develop from?
The metencephalon of the hindbrain
What is the mature cerebellum composed of?
Two cerebellar hemispheres and the vermis
Where does the vermis develop from?
The alar plate and roof plate
Where do the hemispheres develop from?
The alar plate of r1
What is the isthmus?
An organiser
Location of the isthmus organiser at the midbrain/hindbrain boundary (rp = 4th ventricle roof plate). Expression domains of Wnt1 (purple) and Fgf8 (blue)
What do Wnt1 and Fgf8 do to the midbrain and hindbrain?
Organise them
Loss of Fgf8 signalling in early isthmus development results in cell death of both cerebellar and midbrain precursors, affecting the vermis in particular
Loss of Wnt1 produces a very similar phenotype
What are the two germinal centres of the cerebellum?
The rhombic lip (rl) is the edge of rhombomere 1
The ventricular zone (vz) is deeper than the rhombic lip and still part of r1
They create very distinct cell types in the cerebellum
What do we know about the induction and proliferation of the rhombic lip?
Signals coming from the roof plate induce the rhombic lip - e.g. TGFß/BMP
This induces the expression of transcription factors such as Math1 (aka Atoh1) in the early RL cells
Math1 drives cell proliferation in the RL
What do we know about tangential cell migration from the rhombic lip?
First wave of cells migrate to form glutaminergic cells of deep cerebellar nuclei (dcn).
All outputs of cerebellum originate in these nuclei
Second wave form the external germinal layer (egl) (also glutaminergic)
They are still mitotically active!
What do we know about the ventricular zone induction and proliferation?
VZ cells express Ptf1a and make all of the GABAergic neurons in the cerebellum
Induced by the antagonism of TGFß/BMP signals from roof plate by Notch expressed in the VZ precursors
Proliferate at the ventricular edge and then migrate post-mitotically
What do we know about ventricular zone migration?
There is a sequence of cell migration from the VZ
Early cells migrate into the deep cerebellar nuclei (dcn) and form GABAergic cells
The next wave of cells migrating are the purkinje cells and they migrate along Bergmann Glia (radial glial cell type) that is forming around the same time
What are the interactions between EGL and Purkinje cells?
Purkinje cells have migrated along the Bergmann Glia to form the Purkinje plate
They produce Shh which keeps the EGL cells proliferating
Note this is happening postnatally
What do we know about EGL cell differentiation?
The cerebellum is forming recognisable layers
The purkinje cell body is in the PCL but the dendrite are extending dorsally to form the molecular layer.
Above the PCL is the EGL. Cells are still proliferating
Below the PCL is a new layer called the internal germinal layer
What is the internal germinal layer?
The cells in the external germinal layer progressively stop dividing and form a transient inner EGL
They then migrate through the molecular and Purkinje cell layer into the IGL
They use Bergmann glia to do this
Creates adult morphology
Mossy fibre inputs from cerebral cortex complete the architecture
What are the layers of the adult cerebellum?
Molecular layer
PCL
Granule layer aka IGL
- Contains the postmitotic cells that migrated in from the EGL
- Also contain the Bergmann Glia that they used to migrate along
What do we know about development and diseases of the cerebellum?
There are a very large number of cerebellar defects that are seen in vertebrates
What are the very vulnerable stages of cerebellar development?
Early - Specification of hindbrain isthmus formation
Mid - Formation of Rhombic lip and ventricular zone (cell proliferation and migration)
Late - EGL proliferation and differentiation of cells and final migration of cells into IGL
What is cerebellar hypoplasia?
A wide variety of syndromes
The cerebellum is not significantly malformed, just smaller in various aspects; often the vermis
Causes ataxia, vertigo, learning difficulties and other symptoms
What is Dandy-Walker Malformation?
Affects 1:30,000 live births in humans (maybe more)
Hypoplasia of vermis and expansion of 4th ventricle
Found in humans and animals
What is the role of the external germinal layer (EGL)?
EGL cells must responde to Shh and proliferate
This makes the cerebellum bigger
If EGL cells cannot understand the Shh signal, they cannot proliferate
Some of the genes known to be involved in Dandy walker help the EGL cells “hear” Shh.
What do we know about Zic1 and 4 as candidates?
Human mapping studies linked Dandy Walker to 3q24
Zic1 and 4 lie in this region
Pair of zinc finger transcription factors
What do we know about mouse models of Dandy Walker?
There was reduced EGL cell proliferation in Zic1-/- 4-/- from postnatal day 1 (P1)
PCR shows that Shh responsive genes are decreased
Suggests that Zic1/4 are required for EGL cells to interpret the Shh signal from the Purkinje cells
What do we know about cerebellar dysplasia?
Multiple syndromes
Lissencephaly with cerebellar dysplasia
Mapping in humans suggest the REELIN gene is mutated
What is REELIN?
Known to be an extracellular matrix glycoprotein
Spontaneous mouse mutant with ataxia discovered in 1970s (Reeler mouse)
Acts as chemoattractant for migrating neurons
Very important for the correct localisation of purkinje cells in cerebellum
