L14 - Neurotrophins

Question 1

Target-derived trophic factors influence?

Answer 1

Neuronal and synapse survival

Question 2

What is NGF?

Answer 2

The prototype neurotrophin

Question 3

NGF experiment

Answer 3

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

Question 4

Purified protein from snake venom and mouse submaxillary gland

Answer 4

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

Question 5

NGF structure

Answer 5

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

Question 6

How NGF works - Campenot chamber

Answer 6

If NGF present in any chamber - cells ok

If NGF present in only centre chamber – no outward growth

Question 7

NGF affects

Answer 7

Cell survival
Neurite survival
Growth cone guiding

Question 8

How NGF works

Answer 8

Is trophic and tropic

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

Question 9

DRGs take up NGFs and receptors when?

Answer 9

When NGF administered only to their axons

Question 10

What receptors does NGF bind to?

Answer 10

TrkA – high affinity

P75-NTR – low affinity

Question 11

TrkA

Answer 11

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

Question 12

P75-NTR

Answer 12

Promotes cell death or cell survival

Question 13

Neurotrophin family discovery

Answer 13

Biochemistry difficult because levels of neurotrophins low

Limited distribution to support local growth only

Question 14

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

Answer 14

NGF

Question 15

Neurotrophins bind to?

Answer 15

Different receptors - required for survival of different neurons
p75 receptor

Question 16

Different neuron types exhibit different neurotrophin dependency - placodal sensory ganglia

Answer 16

BDNF, NT-3

Question 17

Different neuron types exhibit different neurotrophin dependency - crest derived DRGs

Answer 17

NGF, BDNF or NT3

Question 18

Different neuron types exhibit different neurotrophin dependency - sympathetics

Answer 18

NGF or NT3

Question 19

Specific dependency profiles - can be combinations

Answer 19

Ruffini afferents, BDNF

Merkel NGF, NT3, p75

Question 20

NT3 supports?

Answer 20

Many neurons early in development - on the way to targets

Question 21

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

Answer 21

BDNF and NT3 early
Then NGF
Then NGF or MSP

Question 22

Which animals do not have neurotrophins?

Answer 22

Drosophila and C. elegans

Question 23

Other survival factors?

Answer 23

Glia derived neurotrophic factors
Cytokines
Testosterone

Question 24

Glia derived neurotrophic factors

Answer 24

GDNF supports midbrain dopaminergic neurons

Question 25

Cytokines

Answer 25

Ciliary neurotrophic factor Hepatocyte growth factor Macrophage-stimulating protein

Question 26

Testosterone

Answer 26

Effects on motorneuron pools accounting for sex differences

Question 27

Target derived factors are critical in formation of?

Answer 27

The monosynaptic stretch reflex between motor neurons and proprioceptive sensory neurons

Question 28

Target derived factors determine dendritic morphology and connectivity

Answer 28

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

Question 29

Pea3 knockout

Answer 29

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

Question 30

Circuit completion relies on?

Answer 30

Target feedback Feedback from target determines final patterns of dendritic and axonal connections

Question 31

Er81 knockout

Answer 31

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

Question 32

Muscle-expressed neurotrophin-3 induces expression of?

Answer 32

Transcription factor Er81 by proprioceptors

Question 33

Non-target derived effects of neurotrophins?

Answer 33

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

Question 34

Determinants of survival?

Answer 34

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

Question 35

Coordinated electrical activity

Answer 35

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

Question 36

Synaptic competition

Answer 36

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

Question 37

Determinants of synaptic success

Answer 37

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