L14 - Neurotrophins Flashcards
Target-derived trophic factors influence?
Neuronal and synapse survival
What is NGF?
The prototype neurotrophin
NGF experiment
Implanted sarcomas provoked selective survival of non-placodal sensory and sympathetic neurons
- Not all sarcomas worked
Demonstrated presence of diffusible growth factor
Purified protein from snake venom and mouse submaxillary gland
Antibodies to purified factor (nerve growth factor) blocked DRG growth
NGF structure
7S-NGF = alpha2beta/gamma2 beta NGF subunit - Dimer - Active component - alpha and gamma subunits only found in submax: storage complex
How NGF works - Campenot chamber
If NGF present in any chamber - cells ok
If NGF present in only centre chamber – no outward growth
NGF affects
Cell survival
Neurite survival
Growth cone guiding
How NGF works
Is trophic and tropic
Binds to receptors, is internalised and transported to soma – retrograde support
DRGs take up NGFs and receptors when?
When NGF administered only to their axons
What receptors does NGF bind to?
TrkA – high affinity
P75-NTR – low affinity
TrkA
Ligand induced dimerization and autophosphorylation
Complex downstream pathways
Affects differentiation, growth and movement
P75-NTR
Promotes cell death or cell survival
Neurotrophin family discovery
Biochemistry difficult because levels of neurotrophins low
Limited distribution to support local growth only
Brain-derived neurotrophic factor (BDNF) has high homology with?
NGF
Neurotrophins bind to?
Different receptors - required for survival of different neurons
p75 receptor
Different neuron types exhibit different neurotrophin dependency - placodal sensory ganglia
BDNF, NT-3
Different neuron types exhibit different neurotrophin dependency - crest derived DRGs
NGF, BDNF or NT3
Different neuron types exhibit different neurotrophin dependency - sympathetics
NGF or NT3
Specific dependency profiles - can be combinations
Ruffini afferents, BDNF
Merkel NGF, NT3, p75
NT3 supports?
Many neurons early in development - on the way to targets
Arrival at target often coincides with new expression of neurotrophin by target - trigeminal neurons
BDNF and NT3 early
Then NGF
Then NGF or MSP
Which animals do not have neurotrophins?
Drosophila and C. elegans
Other survival factors?
Glia derived neurotrophic factors
Cytokines
Testosterone
Glia derived neurotrophic factors
GDNF supports midbrain dopaminergic neurons
Cytokines
Ciliary neurotrophic factor
Hepatocyte growth factor
Macrophage-stimulating protein
Testosterone
Effects on motorneuron pools accounting for sex differences
Target derived factors are critical in formation of?
The monosynaptic stretch reflex between motor neurons and proprioceptive sensory neurons
Target derived factors determine dendritic morphology and connectivity
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
Pea3 knockout
Motor neurons innervating cutaneous maximus and latissimus dorsi that have the dendritic morphology of triceps and Pec-innervating motor neurons have aberrant proprioceptive connections
Circuit completion relies on?
Target feedback
Feedback from target determines final patterns of dendritic and axonal connections
Er81 knockout
Failure of Ia proprioceptor central projection to reach ventral horn and form monosynaptic connections
Muscle-expressed neurotrophin-3 induces expression of?
Transcription factor Er81 by proprioceptors
Non-target derived effects of neurotrophins?
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
Determinants of survival?
Coordinated electrical activity pre and post synaptically
Blocking activity stops initiation of cell death mechanisms
- No competition
Coordinated electrical activity
Asynchronous activity leads to weakened synapses and cell death
Synchronous activity leads to strengthened synapses
Synaptic competition
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
Determinants of synaptic success
More active synapse = more neurotrophin taken up by membrane recycling
Greater target mass = more neurotrophin available
