Neuroscience lectures 3-4 - Neurogenesis Flashcards
What are the 3 zones of the neural tube?
1) Ventricular zone
2) Intermediate zone
3) Marginal zone
What does the ventricular zone contain?
Multipotent stem cells
What do the multipotent stem cells in the ventricular zone give rise to?
Neurons and glia
How do the cells of the neural tube divide?
Mitosis
What occurs to cells produced from the multipotent stem cells?
They migrate away to create additional layers - earliest born remain closest to ventricular zone
What are the layers of the cerebellum, from ventricular zone outwards?
1) Ventricular zone
- Intermediate
- Internal granule layer
- Purkinje cell layer
- Marginal zone
- External granule layer
What are the layers of the cerebral cortex from ventricular zone outwards?
- Ventricular zone
- sub-ventricular zone
- indermediate zone
- cortical plate
- marginal zone
- molecular layer
What are the 2 main modes of cell division in the neural tube?
1) Symmetric
2) Asymmetric
What is the purpose of symmetric cell division of stem cells?
- Self renewal/expansion of stem cell population
What are the 2 types of asymmetric stem cell division?
a) Stem cell divides to produce a neuron and another stem cell
b) A neuron and a glial cell
When does neurogenesis start?
Begins during the first few weeks of embryogenesis and continues rapidly after birth?
When does neurogenesis begin to slow?
At around age 1 and a half
How many neurons are added per minute and how many synapses per second during early postnatal development?
- approc 250,000 neurons per minute
- 30,000 synapses/cm^2 of cortex formed per second
How long does neurogenesis continue until?
Early 20’s
Where are adult neural stem cells (NSCs) found?
In the hippocampus
What are adult NSCs involved in?
- Learning and memory
- In the olfactory bulb
In animal models, what is the effect of both an active, interesting environment vs a stressful environment on adult hippocampal neurogenesis?
- Adult hippocampal neurogenesis increases in interesting environment
- Decreases in stressful environment
What could adult NSCs potential be used to treat?
Brain injury or/and neurodegenerative diseases
What is the challenge in using adult NSCs as therapeutics?
To trigger the cells to differentiate into specific neuronal types
What 2 groups of genes are involved in cell signalling to decide neuronal cell fate?
1) Proneural genes
2) Neurogenic genes
What do proneural genes encode?
Basic helix-loop-helic (bHLH) transcription factors e.g Achaete-scute complex, AS-C
What do the neurogenic genes encode?
1) Surfave ligand-receptor pair
- Delta (ligand)
- Notch (receptor)
2) Downstream bHLH transcription factors
e. g C-promoter binding factor CBF-1 and Hairy and E(spl) (HES)
Explain the process of lateral inhibition (delta-notch signalling) in determining cell fate
1) Cell 1 and 2 express same level of notch and delta (equivalent)
2) Cell 1 expresses more delta, increasing notch activation in cell 2 (equivalence lost)
3) In cell 2, cleavage of notch yields Notch-intra which activates bHLH cascade in nucleus - represses achaete-scute
4) Reduction in achaete-scute lowers Delta levels in Cell 2 reducing Notch activation in Cell 1
5) Lower Notch in cell 1 allows achaete-scute levels to rise, increasing Delta expression in cell 1 and notch activation in cell 2
LOW Notch HIGH delta cells (cell 1) are neuronal precursors
HIGH Notch LOW Delta cells (Cell 2) are non-neuronal cells - can become glia
Name the 3 ways the neurons can migrate in the developing embryonic cortex?
1) Migration along radial glial cells (radial migration)
2) Migration along axon tracts (Tangential migration)
3) Migration without a scaffold (Free migration)
When are radial glial cells produced and where do they span from and to?
- Arise early in neurogenesis
- Cell body in the ventricular zone (inner surface)
- Process extends from inner to outer surface and is fixed at each end
- Acts as a track for migrating neurons to move along choo choo
What is nucleokinesis?
Extension of the leading process and movement of the cell body and nucleus into it
Describe nucleokinesis in radial migration
- Neuron extends a leading process in the direction of migration
- Centrosome localises to migrating side of nucleus and extends microtubules (MTs) into the leading process
- MTs form a cage like structure around the nucleus
- Nucleus translocates into the leading process
- The trailing edge retracts
Summary:
1) Leading process moves forward
2) Nucleus moves to leading process
3) Retraction of trailing edge
What molecules are are associated with the MTs?
1) Dynein motor and associated proteins Ndel1 and Lis1
2) Doublecortin (Dcx) which stabilises MTs
How does the nucleus move into the leading process?
With the aid of the dynein-Lis1-Ndel1 complex
What is Lissencephaly?
A group of disorders arising from cortical or general brain malformation
Name 2 disorders that arise from Lis1 mutations
- Type 1 lissencephaly
- Isolated lissencephaly sequence (ILS)
Name a disorder that arises from a doublecortin mutation
X linked ILS
Name a disorder that arises from a Reelin mutation
Autosomal recessive lissencephaly with Cerebellar Hypoplasia (LCH)
Name a disorder that arises from Ndel1 mutations
Microlissencephaly - extreme microcephaly with lissencephaly
What are cortical gyri and sulci and when do they form?
Different parts of a cortical fold
Gyri = top of fold/ridge
Sulci = the groove/depression
- Form as more neurons are produced
What is the appearance of a type 1 lissencephaly brain compared to a normal brain?
- Reduced gyri (fewer folds - smoother)
- Abnormal cortical layers
- Enlarged ventricles
What is the appearance of a microlissencephaly brain?
- Drastic reduction in size
- Absense of corpus callosum
- Limited motor and cognitive development
