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Dev Neurobiology extra > Lecture 14 Neurotophins and death > Flashcards

Lecture 14 Neurotophins and death Flashcards

1
Q

In the embryo, the size of a target correlates with

A

the amount of innervation

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2
Q

Classic expt of Hamburger experiment and results

A

In chick embryo before MN and sensory axons grow out
• Extra target – more neurons/synapses survived
• Less target – less neurons/synapses i.e. corresponding DRG and MN are smaller

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3
Q

Classic expt of Hamburger experiment suggest

A

• Suggests target is providing trophic support to cells (literally ‘food’)
Target size is important

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4
Q

Effects of Hamburger results were due to

A

Changes in cell death

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5
Q

The neurotrophic factor hypothesis

A

Neurons are produced in excess of need and eliminated over time

Neurotrophic factors emanate from targets to promote survival according to tissue size

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6
Q

Why cell death?

What are the trophic factors?

A

More dying cells were seen when the limb bud was removed

Hypothesis was that the tissue was making a trophic factor

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7
Q

Tropic vs trophic

A

NB NOT to be confused with ‘tropic’, meaning turning, (as in chemotropic)

trophic = food

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8
Q

When does cell death occur

A

In all tissues all the time

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9
Q

2 types of cell death

A

Apoptosis

Necrosis

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10
Q

Define apoptosis

A

Programmed cell death

50 billion per day

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11
Q

Too little cell death leads to

A

Exencephaly

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12
Q

Organism for dev apoptosis

A

C.elegans

Nematode worm

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13
Q

How many cells die in C.elegans

A

131 out of 1100

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14
Q

What initiates apoptosis in tadpole tail

A

Surge in thyroid hormone

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15
Q

Define initiator caspases

A

Activated by apoptotic signals

Activates executioner caspases

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16
Q

Define executioner caspases

A

Cleave over 1000 proteins

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17
Q

Describe amplification of proteolytic cleavage

A

1 initiator caspase activates many exec

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18
Q

When are ced genes of c.elegans involved

A

from recognition of apoptotic signal to engulfment of apoptotic cell by phagocytosis

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19
Q

Two classes of gene/protein

A

Anti-apoptotic

Pro-apoptotic

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20
Q

Anti-Apoptotic - loss leads to

A

Loss leads to massive cell death (ie normally prevents cell death)

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21
Q

Pro-Apoptotic - loss leads to

A

Loss leads to excess cells (ie normally required for cell death

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22
Q

Extra elements involved when receive death signals

A

Bax (Bcl-2 associated)

**Caspase 9 (cysteine-aspartic acid protease)

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23
Q

Two classes of caspase

A 
Initiator caspase (e.g. caspase 9) 
Executioner (or effector) caspase (e.g. caspase 1)
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24
Q

Initiator caspase

A

Caspase 9

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25
Executioner caspase
Caspase 1
26
The numbers of cells surviving correlates with
size of the tissue innervated
27
Example showing numbers of cells surviving correlates with the size of the tissue innervated
E.g. dorsal root ganglia
28
Experiment on DRG predicted + evidence to back up
fast growing muscle-like cells might secrete survival factors (limb buds are fast growing) Implanted sarcomas (muscle tumours)* provoked selective survival of sensory and sympathetic neurons i.e. if put more on one side it increases number surviving vs other side
29
What was believed to have been secreted from the tumour
diffusible growth factor (purifired protein)
30
Where else was this diffusible growth factor found
but also found in snake venom and mouse submaxillary gland
31
What did Anti-bodes to the purified factor show
Nerve Growth Factor (NGF) - prototype neurotrophin | AB blocked DRG growth in vivo I.e. this factor promotes DRG growth and survival
32
Structure of NGF
7S-NGF = alpha2betagamma2 | ie 3 subunit types (when isolated from submaxillary gland)
33
Active component of NGF
Beta-NGF | Dimer
34
If axon process have no NGF what happens
Retract as affects cell and neurite survival
35
What can NGF also do
Guide growth cones in vitro so trophic and tropic
36
What support does NGF provide
Retrograde support as NGF binds to R, is internalised and transported to the soma
37
NGF Signalling receptor - high affinity
High affinity receptor TrKA (tropomyosin receptor kinase A) Classic tyrosine kinase receptor, ligand induced dimerization, autophosphorylation etc. Forms signalling endosome that is transported to other regions of the cell
38
Hi affinity receptor – TrkA activates
MAP Kinase pathway to regulate transcription in nucleus (affecting proliferation & differentiation) Akt pathway to inhibit apoptosis and promote cell movement
39
NGF Signalling receptor - low affinity
Lo affinity receptor – p75-NTR | Promotes cell death or cell signalling
40
NGF affects
Tropic effect i.e. guiding as it turns towards NGF source and survival
41
THE NEUROTROPHIN FAMILY - how long before another GF identified in NS
20 years
42
Why is biochem difficult in neurotrophin family
levels of NT’S are low in NS
43
Name anther GF in NS and its relation to NGF
Brain-derived neurotrophic factor (BDNF) | High homology with NGF
44
Name 4 types of BDNF
NT3 and NT4/5 identified (+NT6 and NT7 in fish)
45
How are BDNF secreted
As dimers
46
What do different neurotrophins bind to and what are the outcomes
Different receptors - outcome CONTEXT dependent and depend on BALANCE between diff ligands and their receptors
47
The neurotrophins bind to different receptors for... | Example
the survival of different neurons | Pro NGF --> apoptosis, NGF --> cell survival
48
What do all receptors bind to
p75-NTR
49
Different neuron types exhibit
different neurotrophin (NT) dependencies
50
Placodal sensory ganglia e.g. nodose prefer
BDNF / NT3
51
Crest-derived DRGs have subpopulations that respond to NGF, BDNF or NT3
NGF, BDNF or NT3
52
Sympathetics respond to
NGF or NT3 but not BDNF
53
Specific Dependency profiles (i.e. neurons can be dependent on combinations of NTs) examples
Ruffini afferents, BDNF | Merkel Discs NGF, NT3, p75
54
Do Differential Dependence change with time
YES Newly born neurons may have no dependency initially NT3 supports many neuronal types early in development I.e. on way to target ``` Arrival at target often coincides with new expression of neurotrophic factors by target e.g. trigeminal neurons need BDNF and NT3 early then NGF as target reached then NGF and/or MSP* ```
55
However the neurotrophic factors involved can belong to different families - examples
Glia-derived neurotrophic factors (GDNFs) E.g. GDNF supports midbrain dopaminergic neuron survival Cytokines: Ciliary Neurotrophic Factor (CNTF) Hepatocyte Growth Factor (HGF) Macrophage Stimulating Protein (MSP)
56
Why Cell Death?
Neurotrophic factor hypothesis: effectively ‘size control’. Keeping tissue size and innervation in proportion Removal of transient structures: E.g. subplate neurons in cortex, Ti1 axons in grasshopper limb: both are scaffolds for later axons and die once their job is done (see axon guidance lectures)
57
Where does pruning occur
e.g. cortico-spinal and cortico-collicular projections are initially similar, but are differentially pruned
58
What features are shared between pruning and apoptosis
Cell fragmentation | Clearing by phagocytosis
59
What is also involved in axon pruning and degradation
Caspase 6 Activated by Amyloid precursor protein shed from axons after NGF deprivation Since APP is causally implicated in Alzheimer’s disease, suggests that these pathways may be good targets for therapies for neurodegenerative disease
60
Example of death receptor
DR6 belongs to the Tumour Necrosis Factor (TNF) family
61
Death receptors common with p75-NTR as
have intracellular ‘death domain’ (DD) which can directly initiate caspase-mediated Programmed Cell Death (PCD)
62
Difference between p75-NTR and death receptors
Unlike the Death Receptors, which initiate cell death upon ligand binding, p75-NTR initiates cell death in the absence of ligand and so is called a ‘Dependence Receptor’
63
Examples of dependence receptors
Ptch1, DCC, Trk, EphA4

Dev Neurobiology extra (6 decks)

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