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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
Q

Executioner caspase

A

Caspase 1

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26
Q

The numbers of cells surviving correlates with

A

size of the tissue innervated

27
Q

Example showing numbers of cells surviving correlates with the size of the tissue innervated

A

E.g. dorsal root ganglia

28
Q

Experiment on DRG predicted + evidence to back up

A

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
Q

What was believed to have been secreted from the tumour

A

diffusible growth factor (purifired protein)

30
Q

Where else was this diffusible growth factor found

A

but also found in snake venom and mouse submaxillary gland

31
Q

What did Anti-bodes to the purified factor show

A

Nerve Growth Factor (NGF) - prototype neurotrophin

AB blocked DRG growth in vivo I.e. this factor promotes DRG growth and survival

32
Q

Structure of NGF

A

7S-NGF = alpha2betagamma2

ie 3 subunit types (when isolated from submaxillary gland)

33
Q

Active component of NGF

A

Beta-NGF

Dimer

34
Q

If axon process have no NGF what happens

A

Retract as affects cell and neurite survival

35
Q

What can NGF also do

A

Guide growth cones in vitro so trophic and tropic

36
Q

What support does NGF provide

A

Retrograde support as NGF binds to R, is internalised and transported to the soma

37
Q

NGF Signalling receptor - high affinity

A

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
Q

Hi affinity receptor – TrkA activates

A

MAP Kinase pathway to regulate transcription in nucleus (affecting proliferation & differentiation)

Akt pathway to inhibit apoptosis and promote cell movement

39
Q

NGF Signalling receptor - low affinity

A

Lo affinity receptor – p75-NTR

Promotes cell death or cell signalling

40
Q

NGF affects

A

Tropic effect i.e. guiding as it turns towards NGF source and survival

41
Q

THE NEUROTROPHIN FAMILY - how long before another GF identified in NS

A

20 years

42
Q

Why is biochem difficult in neurotrophin family

A

levels of NT’S are low in NS

43
Q

Name anther GF in NS and its relation to NGF

A

Brain-derived neurotrophic factor (BDNF)

High homology with NGF

44
Q

Name 4 types of BDNF

A

NT3 and NT4/5 identified (+NT6 and NT7 in fish)

45
Q

How are BDNF secreted

A

As dimers

46
Q

What do different neurotrophins bind to and what are the outcomes

A

Different receptors - outcome CONTEXT dependent and depend on BALANCE between diff ligands and their receptors

47
Q

The neurotrophins bind to different receptors for…

Example

A

the survival of different neurons

Pro NGF –> apoptosis, NGF –> cell survival

48
Q

What do all receptors bind to

A

p75-NTR

49
Q

Different neuron types exhibit

A

different neurotrophin (NT) dependencies

50
Q

Placodal sensory ganglia e.g. nodose prefer

A

BDNF / NT3

51
Q

Crest-derived DRGs have subpopulations that respond to NGF, BDNF or NT3

A

NGF, BDNF or NT3

52
Q

Sympathetics respond to

A

NGF or NT3 but not BDNF

53
Q

Specific Dependency profiles (i.e. neurons can be dependent on combinations of NTs) examples

A

Ruffini afferents, BDNF

Merkel Discs NGF, NT3, p75

54
Q

Do Differential Dependence change with time

A

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
Q

However the neurotrophic factors involved can belong to different families - examples

A

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
Q

Why Cell Death?

A

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
Q

Where does pruning occur

A

e.g. cortico-spinal and cortico-collicular projections are initially similar, but are differentially pruned

58
Q

What features are shared between pruning and apoptosis

A

Cell fragmentation

Clearing by phagocytosis

59
Q

What is also involved in axon pruning and degradation

A

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
Q

Example of death receptor

A

DR6 belongs to the Tumour Necrosis Factor (TNF) family

61
Q

Death receptors common with p75-NTR as

A

have intracellular ‘death domain’ (DD) which can directly initiate caspase-mediated Programmed Cell Death (PCD)

62
Q

Difference between p75-NTR and death receptors

A

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
Q

Examples of dependence receptors

A

Ptch1, DCC, Trk, EphA4

Dev Neurobiology extra (6 decks)

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