Transcript NGF is the trophic factor that promotes cell survival

Life and Death for Neurons
We lose 20-80% of our neurons during development
Most neurons die right around the time
that axons are invading the target
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Why do neurons live or die?
Viktor Hamburger, 1920s
Expt: Look at the effect of removing or adding a limb on motor neuron
survival in the spinal cord of the Xenopus frog
Result: Adding a limb increases neuronal survival, while removing one
reduces it.
Model: The target is making something in limited quantities that promotes
cell survival.
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Nobel 1986: Rita Levi-Montalcini and Stanley Cohen
Identification of nerve growth factor
Experiment :
Transplant mouse sarcoma tumors
near limb bud.
Result: More neurons in the dorsal root ganglia survive.
What makes neurons survive?
They isolated the factor and called it nerve growth
factor.
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How Nerve Growth Factor was isolated
1. Develop an assay: cultured Dorsal Root Ganglia in a dish
Added tumor extract,
neuron outgrowth is dramatically enhanced
2. Identify a rich source of NGF: purified NGF from snake venom
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Does NGF really promote cell survival?
DRG +
Sympathetic
Neurons
They DIE
+ NGF
They SURVIVE
venom + NGF Ab
They DIE
 NGF is the trophic factor that promotes cell survival
 NGF is made by the target neuron
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The Neurotrophic Hypothesis
• The target cells release a factor that promotes cell survival
• This factor is found in limiting quantities
• Cells compete to get enough factor to survive
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There are many different trophic factors
•Neurotrophins
•NGF TrkA Receptor
•BDNF  TrkB Receptor
•NT3 TrkC Receptor
They all also bind
the p75 receptor
•NT4/5 TrkB Receptor
•TGF-Beta Family
•Interleukin – 6 related cytokins
•FGFs
•SHH
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Neurotrophins act through
receptor tyrosine kinase signaling cascades
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Signal transduction for Neurotrophins
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Other actions of neurotrophins
• Neuronal survival
• Nerve growth
• Nerve sprouting
• Differentiation
• Modulation of synaptic transmission
• Electrical properties
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The Neurotrophic Hypothesis:
neurons compete for limiting amounts of a neurotrophin
some neurons survive, other neurons die
A
Neurons approach target
Target source of
neurotrophic factor
Degenerating neuron
Limited supply of
neurotrophic factor
B
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How do neurons die?
Two kinds of cell death
1) Necrosis
Death by accident, ie trauma to tissue
2) Apoptosis
Death by design
Controlled cellular self-destruction
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The process of Apoptosis
Normal Cell
Cell shrinks away from
neighbours
Plasma membrane blebbing
Cytoplasmic and nuclear condensation
Chromatin condenses
Nuclear and cellular
fragmentation
Apoptotic Bodies
Phagocytosis
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Morphological Differences between
Apoptosis and Necrosis
Apoptosis
vs
Necrosis
Nuclei
Dense Condensation
of Chromatin
Irregular Chromatin
Clumping
Cytoplasmic
Organelles
Morphologically Intact
Disrupted
Cell
Membrane
Apoptotic Bodies,
Blebbing
Blebbing and Loss of
integrity
Cell Volume
Cells shrink
Cells swell
DNA
Cleaved into fragments
No damage
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Morphological Appearance of Apoptosis
A
A
A
A
Nucleus is fragmented, blebby
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Morphological appearance of apoptosis
DNA is fragmented into 180 bp pieces
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What molecules cause apoptosis?
C. elegans cell death Program
Complete lineage description of all 1090 cells
- 113 cells die during embryogenesis
- 18 cells die later in life
Mutagen
Increased survival
Decreased survival
Mutated Gene
ced3
ced4
ced9(g.o.f)
Isolate
gene
Phenotype
blocked all 131 embryonic cell deaths
blocked all 131 embryonic cell deaths
absence of cell death, embryonic lethality
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The apoptotic pathway is conserved in worms and humans
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Most of the molecules involved in apoptosis are novel
CED3 caspase is a cysteine protease….cleaves proteins
CED4 adaptor activates CED3
CED9 inhibits CED4
EGL-1 inhibits CED9
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Do trophic factors inhibit apoptosis?
A
Neurons approach target
Target source of
neurotrophic factor
Degenerating neuron
Limited supply of
neurotrophic factor
B
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Neurotrophins increase Bcl-2 expression to inhibit apoptosis
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P75 on its own can activate the apoptotic pathway
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Why is apoptosis used during development?
1. sculpting structures
2. deleting unneeded structures
3. controlling cell numbers
4. eliminating non-functional or
harmful cells
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Diseases Associated with Deregulated Apoptosis
Increased Apoptosis
AIDS
Neurodegernative disorders
Alzeheimer’s disease,
Parkinson’s disease,
Amyotrophic lateral sclerosis
Retinitis pigmentosa
Myelodysplastic syndromes
Aplastic anaemia
Ischaemic Injury
Myocardial infarction,
Stroke,
Reperfusion injury
Toxin-Induced liver disease
Alcohol
Inhibition of Apoptosis
Cancer
Follicular lymphomas
carinomas with p53 mutations
hormone dependent tumours:
breast cancer, prostate cancer,
ovarian cancer
Autoimmune Disorders
Systemic lupus erythematosus
Immune-mediated glomerulonephritus
Viral Infections
Herpesvirus, poxvirus, adenovirus
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Why does a neuron live or die?
1. Neurotrophins promote cell survival
by inhibiting apoptosis
2. Apoptosis allows cell death to occur
without harming nearby cells
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