Lecture 12- Neuronal migration in brain development III (cerebellum and RMS) Flashcards
What are the main functions of the cerebellum?
-coordinates motor patterns by monitoring and modifying motor programs
What percentage of all the neurons in the brain are in the cerebellum?
- 50%
- arranged in a highly ordered fashion
What are the cell types in the cerebellum? (4)
- Purkinje cells (PC)
- Granule cells (GC)
- Stellate cells (S)
- Golgi epithelial cells (GEC)
What are the three layers of the cerebellum?
- Molecular layer (ML)
- Purkinje cell layer (PCL)
- Granular layer (GL)
- cerebellum has laminated structure so needs migration during development

What are the Purkinje cells?
-projection neurons and the other layers contain various interneurons (stellate, granule, basket and golgi epithelial cell)

When does the cerebellum (cerebellar cortex) undergo morphogenetic changes?
-during development from E11 to postnatal day (P) 7
- tiny structure between midbrain and hindbrain at first (the cerebellum) then grows
- P- postnatal (birth)
- the adult picture= granular cell layer is darkly stained(in adult called inner granular layer)
- the migration occurs P0-P7 so after birth

What is the cerebellum derived from?
- from the rhombic lip situated in the dorsal metencephalon (hindbrain) adjacent to the fourth ventricle
- this layer of tissue that gives rise to the cerebellum is called external germinal layer

What is the external germinal layer (EGL)?
- this layer generates granule cells that migrate inwardly in a radial manner with the assistance of radial glia fibers of the Golgi epithelial cells
- the EGL is a transitory developmental structure not present in the adult
- this is involved in the development of the cerebellum

What are the domains of the developing cerebellum? (5)
- the developing cerebellum can be subdivided into domains:
1. External granule (germinal) layer
2. Molecular layer
3. Purkinje cell layer
4. Internal granule cell layer
5. Ventricular zone

What are the two zones in the developing cerebellum where cells are generated and what cells are born where?
- Ventricular zone= Purkinje cells are born here
- External granule (germinal zone)= Inhibitory granule neurons born here

What is the Purkinje cell migration in the cerebellum like?
-they are born in the ventricular zone and migrate outward

What is the migration of inhibitory granule neurons in the developing cerebellum like?
- born in the external granule layer (EGL)
- migrate through the molecular layer past the Purkinje cells to form the internal granule layer
- so during development have two granule layers, as and adult only he internal one remains

What do defects in the VLDLR gene lead to?
- pontocerebellar hypoplasia
- cerebellum shrinks and often doesn’t form at all

Does Lissencephaly have an effect on the cerebellum?
- yes
- when mutations in RELN (gene coding for Reelin) then big defects in the cerebellar lamination and formation
What are the mutants shown in the picture?

scm= scrambler is a natural mutant of the Dab1 protein
A= +/scm: heterozygote, control
B= scm/scm: Dab1 null mutant
C= rl/rl: Reelin null mutant
D and E compare the effects of B and C- very similar, thus Dab1 and Reelin are part of the same pathway
- Dab is an intracellular adaptor molecule for Reelin signalling
- these mutations lead to significant defects in the cerebellum
What are the two cerebellar abnormalities that Reelin mutations lead to?
- Purkinje cells form clumps and not a single layer
- Granule cells remain in the external layer and do not migrate past the Purkinje cells
What is the role of Reelin in cerebellar neuronal migration?
- Reelin released by external granule layer situated on the outer part.= Purkinje cells migrate towards these cells
- This is very similar to the cortex where Reelin is expressed by Cajal Retzius cells in the Marginal Zone (only similar to the Purkinje cell migration)
- in the cerebellum have cell moving towards reelin (Purkinje cells) and away from it (granule cells)
- when Reelin is absent the migration does not occur
- Reelin provides orientation cues

How is the RMS (rostral migratory stream) different to the othe rmigrations we have discussed?
- different migration, not setting up a structure in the brain, providing neurons for another part of the brain
- interneurons migrate from the lateral ventricle to the olfactory bulb via the RMS
- adult neurogenesis moment, this happens in adults too (based on rodent models)
- created in lateral ventricle (subventricular zone = diff to cortex) and migrate
- in humans there are not as many as in the rodents
- the neurons will enter the olfactory bulb only in a particular orientation, lot of guidance cues involved

What are the 2 neuogenic regions in the adult mammalian brain?
- Subgranular zone of the dentate gyrus in the hippocampus
- Subventricular zone (SVZ) of the lateral ventricle, post-mitotic cells migrate along the rostral migratory stream (RMS) to form interneurons in the olfactory bulb

What do olfactory bulb interneurons arise from?
- a pool of proliferating cells that reside in the SVZ of the walls of the lateral ventricle
How do the olfactory bulb interneurons migrate from the lateral ventricle wall?
- cells migrate tangentially and use a specialised form of neuronal migration called chain migration (this is different from the glial or guidance- guidance migration)
- migrating cells have an elongated morphology with a leading process and growth-cone like tip similar to those found on migrating interneurons
- cell adhesion molecules mediate the cell-cell interaction during migration, the cells stick together via polysialyted cell adhesion molecules (PSA-NCAM)
How is chain migration possible?
- the cells literally have to be in contact with other cells in order to migrate
- stick together using PSA-NCAM (polysialyted neural cell adhesion molecule)
Is the morpology of the migrating OB (olfactory bulb) interneuron similar to the migrating cortical interneuron?
-yes but the OB interneuron has less branching
How can the chain migration in RMS be monitored?
- using In vitro explant cultures, can thus monitor migration and examine factors regulating this process
- picture: neurons migrate away from the original RMS explant (dotted lines) and form cell aggregations resembling chains






