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Developmental Neurobiology > L14 - Neurotrophins > Flashcards

L14 - Neurotrophins Flashcards

1
Q

Target-derived trophic factors influence?

A

Neuronal and synapse survival

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2
Q

What is NGF?

A

The prototype neurotrophin

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3
Q

NGF experiment

A

Implanted sarcomas provoked selective survival of non-placodal sensory and sympathetic neurons
- Not all sarcomas worked
Demonstrated presence of diffusible growth factor

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4
Q

Purified protein from snake venom and mouse submaxillary gland

A

Antibodies to purified factor (nerve growth factor) blocked DRG growth

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5
Q

NGF structure

A 
7S-NGF = alpha2beta/gamma2
beta NGF subunit 
- Dimer
- Active component
- alpha and gamma subunits only found in submax: storage complex
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6
Q

How NGF works - Campenot chamber

A

If NGF present in any chamber - cells ok

If NGF present in only centre chamber – no outward growth

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7
Q

NGF affects

A

Cell survival
Neurite survival
Growth cone guiding

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8
Q

How NGF works

A

Is trophic and tropic

Binds to receptors, is internalised and transported to soma – retrograde support

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9
Q

DRGs take up NGFs and receptors when?

A

When NGF administered only to their axons

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10
Q

What receptors does NGF bind to?

A

TrkA – high affinity

P75-NTR – low affinity

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11
Q

TrkA

A

Ligand induced dimerization and autophosphorylation
Complex downstream pathways
Affects differentiation, growth and movement

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12
Q

P75-NTR

A

Promotes cell death or cell survival

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13
Q

Neurotrophin family discovery

A

Biochemistry difficult because levels of neurotrophins low

Limited distribution to support local growth only

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14
Q

Brain-derived neurotrophic factor (BDNF) has high homology with?

A

NGF

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15
Q

Neurotrophins bind to?

A

Different receptors - required for survival of different neurons
p75 receptor

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16
Q

Different neuron types exhibit different neurotrophin dependency - placodal sensory ganglia

A

BDNF, NT-3

17
Q

Different neuron types exhibit different neurotrophin dependency - crest derived DRGs

A

NGF, BDNF or NT3

18
Q

Different neuron types exhibit different neurotrophin dependency - sympathetics

A

NGF or NT3

19
Q

Specific dependency profiles - can be combinations

A

Ruffini afferents, BDNF

Merkel NGF, NT3, p75

20
Q

NT3 supports?

A

Many neurons early in development - on the way to targets

21
Q

Arrival at target often coincides with new expression of neurotrophin by target - trigeminal neurons

A

BDNF and NT3 early
Then NGF
Then NGF or MSP

22
Q

Which animals do not have neurotrophins?

A

Drosophila and C. elegans

23
Q

Other survival factors?

A

Glia derived neurotrophic factors
Cytokines
Testosterone

24
Q

Glia derived neurotrophic factors

A

GDNF supports midbrain dopaminergic neurons

25
Q

Cytokines

A

Ciliary neurotrophic factor
Hepatocyte growth factor
Macrophage-stimulating protein

26
Q

Testosterone

A

Effects on motorneuron pools accounting for sex differences

27
Q

Target derived factors are critical in formation of?

A

The monosynaptic stretch reflex between motor neurons and proprioceptive sensory neurons

28
Q

Target derived factors determine dendritic morphology and connectivity

A

Motor neurons innervating triceps and pectoral muscles - monosynaptic connections directly with proprioceptors
Motor neurons innervating cutaneous maximus and latissimus dorsi - polysynaptic input from interneurons
Controlled by GDNF secreted from cutaneous maximus and latissimus dorsi
- Turns on transcription factor Pea3 in motor neurons

29
Q

Pea3 knockout

A

Motor neurons innervating cutaneous maximus and latissimus dorsi that have the dendritic morphology of triceps and Pec-innervating motor neurons have aberrant proprioceptive connections

30
Q

Circuit completion relies on?

A

Target feedback

Feedback from target determines final patterns of dendritic and axonal connections

31
Q

Er81 knockout

A

Failure of Ia proprioceptor central projection to reach ventral horn and form monosynaptic connections

32
Q

Muscle-expressed neurotrophin-3 induces expression of?

A

Transcription factor Er81 by proprioceptors

33
Q

Non-target derived effects of neurotrophins?

A

Lack of synaptic input can cause loss of target neurons
- E.g. somatosensory barrels
Anterograde transport of neurotrophins
- E.g. NT3 in retinal ganglion neurons
Paracrine effects
- Early DRGs in single cell cultures release NT3
- Promotes differentiation

34
Q

Determinants of survival?

A

Coordinated electrical activity pre and post synaptically
Blocking activity stops initiation of cell death mechanisms
- No competition

35
Q

Coordinated electrical activity

A

Asynchronous activity leads to weakened synapses and cell death
Synchronous activity leads to strengthened synapses

36
Q

Synaptic competition

A

Initially, multiple motor neurons innervate a single muscle fibre

  • This is reduced by competition to a single motor neuron innervating a single fibre
  • Blocking activity leads to reduction in synapse loss
37
Q

Determinants of synaptic success

A

More active synapse = more neurotrophin taken up by membrane recycling
Greater target mass = more neurotrophin available

Developmental Neurobiology (17 decks)

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