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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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Expt: Look at the effect of removing or adding a limb on 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.
Viktor Hamburger, 1920s
Why do neurons live or die?
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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.
Nobel 1986: Rita Levi-Montalcini and Stanley Cohen
Identification of nerve growth factor
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How Nerve Growth Factor was isolated
1. Develop an assay: cultured Dorsal Root Ganglia in a dishAdded tumor extract, neuron outgrowth is dramatically enhanced
2. Identify a rich source of NGF: purified NGF from snake venom
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NGF is the trophic factor that promotes cell survival
NGF is made by the target neuron
DRG + Sympathetic Neurons
They DIE
They SURVIVE+ NGF
They DIE
venom + NGF Ab
Does NGF really promote cell survival?
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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
•NT4/5 TrkB Receptor
•TGF-Beta Family
•Interleukin – 6 related cytokins
•FGFs
•SHH
They all also bind the p75 receptor
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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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A
Ne uro ns a p p ro a c h ta rg e t
De g e ne ra ting ne uro n
Ta rg e t so urc e o f ne uro tro p hic fa c to r
Lim ite d sup p ly o f ne uro tro p hic fa c to r
B
The Neurotrophic Hypothesis: neurons compete for limiting amounts of a neurotrophin
some neurons survive, other neurons die
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How do neurons die?
Two kinds of cell death
1) NecrosisDeath by accident, ie trauma to tissue
2) Programmed Cell Death (Apoptosis)Death by designControlled cellular self-destruction
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Normal Cell
Cell shrinks away from neighbours
Plasma membrane blebbingCytoplasmic and nuclear condensation
Chromatin condenses
Nuclear and cellular fragmentation
Apoptotic Bodies
Phagocytosis
The process of Programmed Cell Death (PCD)
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PCD Necrosis
Nuclei Chromatin condensation, fragmentation
Irregular chromatin clumping
Cytoplasmic Organelles
Membranes intact Disrupted
vs
Morphological Differences between
Programmed Cell Death and Necrosis
DNA Cleaved into fragments No damage
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C. elegans cell death Program
Complete lineage description of all 1090 cells - 131 cells die during development
Mutagen
Increased survival
Decreased survival
Isolate gene
Mutated Gene Phenotype ced3 blocked all 131 embryonic cell deaths ced4 blocked all 131 embryonic cell deaths ced9(g.o.f) absence of cell death, embryonic lethality
What molecules cause Programmed Cell Death?
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Most of the molecules involved in PCD 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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A
Ne uro ns a p p ro a c h ta rg e t
De g e ne ra ting ne uro n
Ta rg e t so urc e o f ne uro tro p hic fa c to r
Lim ite d sup p ly o f ne uro tro p hic fa c to r
B
Do trophic factors inhibit Programmed Cell Death?
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Overexpression (OE) of Bcl-2 gives bigger brains
12% volume increase in Bcl-2 OE brains
Normal
Bcl-2 OE
bcl-2 OE normal
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Why is PCD 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
AIDSNeurodegernative disorders Alzeheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis Retinitis pigmentosaMyelodysplastic syndromes Aplastic anaemiaIschaemic Injury Myocardial infarction, Stroke, Reperfusion injuryToxin-Induced liver disease Alcohol
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
Inhibition of Apoptosis
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