Download Lecture V. Cell Birth and Death

Lecture V. Cell Birth and
Death
Bio 3411
Wednesday
September 15, 2010
September 15, 2010
Lecture V. Cell Birth & Death
1
Readings
NEUROSCIENCE: 4th ed, pp 596-609
(end of Chapter 23: Construction of Neural Circuits)
References posted:
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†Abbott,
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†Berry,
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†Cohen,
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†Hengartner,
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†Hollyday,
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†Raff,
A. (2009). Neuroscience: One hundred years of Rita. Nature, 458(7238), 564-567.
D. (2006). Apoptosis and signal transduction.
http://www.wehi.edu.au/education/wehi-tv/?page=2.
S. (1987). Autobiography.
http://nobelprize.org/nobel_prizes/medicine/laureates/1986/cohen-autobio.html
M. O. (2000). The biochemistry of apoptosis. Nature, 407(6805), 770-776.
M. (2001). Viktor Hamburger (1900-2001): A rememberance. Developmental
Biology, 236(1), 1-2.
M. (1998). Cell suicide for beginners. Nature, 396(6707), 119-122.
______________________
†(pdfs
on course websites: [http://artsci.wustl.edu/~bio3411/] &
[http://www.nslc.wustl.edu/courses/Bio3411/bio3411.html])
September 15, 2010
Lecture V. Cell Birth & Death
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Cited A
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Acehan, D., Jiang, X., Morgan, D. G., Heuser, J. E., Wang, X., & Akey, C. W. (2002). Three-dimensional
structure of the apoptosome: implications for assembly, procaspase-9 binding, and activation. Mol
Cell, 9(2), 423-432.
Brenner, S. (1973). The genetics of behaviour. Br Med Bull, 29(3), 269-271.
Cleary, M. L., Smith, S. D., & Sklar, J. (1986). Cloning and structural analysis of cDNAs for bcl-2
and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell, 47(1),
19-28.
Cohen, S., Levi-Montalcini, R., & Hamburger, V. (1954). A Nerve Growth-Stimulating Factor
Isolated from Sarcom as 37 and 180. Proc Natl Acad Sci U S A, 40(10), 1014-1018.
Cowan, W. M., & Wenger, E. (1967). Cell loss in the trochlear nucleus of the chick during normal
development and after radical extirpation of the optic vesicle. J Exp Zool, 164(2), 267-280.
Ellis, R. E., & Horvitz, H. R. (1991). Two C. elegans genes control the programmed deaths of
specific cells in the pharynx. Development, 112(2), 591-603.
Ellis, R. E., Yuan, J. Y., & Horvitz, H. R. (1991). Mechanisms and functions of cell death. Annu
Rev Cell Biol, 7, 663-698.
Fesik, S. W. (2000). Insights into programmed cell death through structural biology. Cell, 103(2),
273-282.
Gross, A., McDonnell, J. M., & Korsmeyer, S. J. (1999). BCL-2 family members and the
mitochondria in apoptosis. Genes Dev, 13(15), 1899-1911.
Haldar, S., Reed, J. C., Beatty, C., & Croce, C. M. (1990). Role of bcl-2 in growth factor triggered
signal transduction. Cancer Res, 50(22), 7399-7401.
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Lecture V. Cell Birth & Death
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Cited B
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Hamburger, V. (1958). Regression versus peripheral control of differentiation in motor hypoplasia.
Am J Anat, 102(3), 365-409.
Hamburger, V. (1975). Cell death in the development of the lateral motor column of the chick
embryo. J Comp Neurol, 160(4), 535-546.
Hamburger, V. (1977). The developmental history of the motor neuron. Neurosci Res Program
Bull, 15 Suppl, iii-37.
Kerr, J. F., Wyllie, A. H., & Currie, A. R. (1972). Apoptosis: a basic biological phenomenon with
wide-ranging implications in tissue kinetics. Br J Cancer, 26(4), 239-257.
Korsmeyer, S. J. (1992). Bcl-2: an antidote to programmed cell death. Cancer Surv, 15, 105-118.
Landmesser, L., & Pilar, G. (1974). Synaptic transmission and cell death during normal ganglionic
development. J Physiol, 241(3), 737-749.
Levi-Montalcini, R., & Hamburger, V. (1951). Selective growth stimulating effects of mouse
sarcoma on the sensory and sympathetic nervous system of the chick embryo. J Exp Zool, 116(2),
321-361.
Levi-Montalcini, R., Meyer, H., & Hamburger, V. (1954). In vitro experiments on the effects of
mouse sarcomas 180 and 37 on the spinal and sympathetic ganglia of the chick embryo. Cancer
Res, 14(1), 49-57.
Schlesinger, P. H., Ferdani, R., Liu, J., Pajewska, J., Pajewski, R., Saito, M., Shabany, H., &
Gokel, G. W. (2002). SCMTR: a chloride-selective, membrane-anchored peptide channel that
exhibits voltage gating. J Am Chem Soc, 124(9), 1848-1849.
Sulston, J. E., & Horvitz, H. R. (1977). Post-embryonic cell lineages of the nematode,
Caenorhabditis elegans. Dev Biol, 56(1), 110-156.
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Cited C
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Sulston, J. E., Schierenberg, E., White, J. G., & Thomson, J. N. (1983). The embryonic cell
lineage of the nematode Caenorhabditis elegans. Dev Biol, 100(1), 64-119.
Vaux, D. L., Cory, S., & Adams, J. M. (1988). Bcl-2 gene promotes haemopoietic cell survival and
cooperates with c-myc to immortalize pre-B cells. Nature, 335(6189), 440-442.
White, J. G., Horvitz, H. R., & Sulston, J. E. (1982). Neurone differentiation in cell lineage mutants
of Caenorhabditis elegans. Nature, 297(5867), 584-587.
Wiesmann, C., Ultsch, M. H., Bass, S. H., & de Vos, A. M. (1999). Crystal structure of nerve
growth factor in complex with the ligand-binding domain of the TrkA receptor. Nature, 401(6749),
184-188.
Xue, D., & Horvitz, H. R. (1997). Caenorhabditis elegans CED-9 protein is a bifunctional cell-death
inhibitor. Nature, 390(6657), 305-308.
Xue, D., Shaham, S., & Horvitz, H. R. (1996). The Caenorhabditis elegans cell-death protein
CED-3 is a cysteine protease with substrate specificities similar to those of the human CPP32
protease. Genes Dev, 10(9), 1073-1083.
Yang, X., Chang, H. Y., & Baltimore, D. (1998). Essential role of CED-4 oligomerization in CED-3
activation and apoptosis. Science, 281(5381), 1355-1357.
Yuan, J. Y., & Horvitz, H. R. (1990). The Caenorhabditis elegans genes ced-3 and ced-4 act cell
autonomously to cause programmed cell death. Dev Biol, 138(1), 33-41.
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What the last Lecture was about
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Mesoderm induces neuroectoderm in overlying ectoderm that gives rise to
neuronal or epidermal cells.
The “default” state of neuroectodermal cells is neuronal.
Neuroectoderm secretes Bone Morphogenic Protein-4 (BMP-4), a
signaling molecule that blocks the neuronal fate in neighboring
neuroectodermal cells.
Mesoderm secretes proteins - Chordin, Noggin, Follistatin - that block
BMP-4 and neuroectodermal cells continue as neuronal progenitors.
This inductive mechanism is conserved between vertebrates and
invertebrates.
These, and other similar, signaling mechanisms are used by the developing
nervous system to control other events later in development.
BMP-4 is a member of the Transforming Growth Factor-beta (TGF-β) family
of signaling molecules.
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What this Lecture is about
• Cell Death – Necrosis vs Apoptosis
• Promoting growth and survival – “trophism”
• Inhibition of the “death mechanism”
• Broader implications: neuroembryology; cancer
• Different critters - Same genes
• Molecular models
• Connection of Trophic Factors to cell death
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Apoptosis
Kerr, J. F., et al.,(1972)
from Greek
“apo” meaning “separation”
&
“ptosis” for “falling off”
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Types of Cell Death
• Not Self-Initiated
(Provoked)
• Not Stereotypic
• Can Be Slow
• “Messy”
(injury can spread)
Apoptosis
• Cell-Autonomous
• Stereotypic
• Rapid
• “Clean”
(dead cells eaten)
Necrosis
(Programmed)
Ellis, R. E., et al., (1991)
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Lecture V. Cell Birth & Death
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Removing a neuron’s targets, leads to its death
Hamburger, V. (1958,1977)
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Deprived
Lecture V. Cell Birth & Death
Normal
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Neuronal death is central for normal NS development
Hamburger, (1975);
Landmesser & Pilar, (1974);
Cowan & Wenger, (1967)
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Lecture V. Cell Birth & Death
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Neuron survival correlates
with target innervation
Motor neurons
Target
Muscles
Axon
Outgrowth
Development
Progresses
Target
Innervation
Not all neurons
innervate targets
Neuronal Loss
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Lecture V. Cell Birth & Death
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Target innervation determines which
neurons survive
Development
Progresses
More targets
(more neurons)
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Lecture V. Cell Birth & Death
Fewer targets
(fewer neurons)
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Mouse tumor (sarcoma) transplanted next to developing chick
spinal cord causes axon sprouting consistent with a diffusible
factor - a nerve growth factor
Levi-Montalcini, R., & Hamburger, V. (1951)
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A quantitative functional assay for Nerve Growth Factor (NGF)
activity, using explanted cultures of sensory ganglia
Levi-Montalcini, et al. (1954);
Cohen, S., et al. (1954)
Viktor
Hamburger
Rita
Levi-Montalcini
Stanley
Cohen
Hollyday, M. (2001);
Abbott, A. (2009).
Cohen, S. (1987)
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Lecture V. Cell Birth & Death
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NGF is the founding member of a large gene family
of Neurotrophins (NTs), distantly related to insulin
NGF binds
as a dimer
to its receptor
Wiesmann, C., et al. (1999)
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NGF/Neurotrophins Signal through
Trk (tyrosine kinase) Receptors
NGF/NT
Trk Receptors
(TrkA, TrkB, TrkC, p75)
Multiple Signaling
Pathways
Apoptosis
pathway
(PIK3/AKT kinase)
Via kinases and
scaffolding proteins
(PLC/PKC kinase)
(Ras/MAP kinase)
Intracellular Ca+2
release, modulation
of ion channels
Gene Activation/
Repression
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C. elegans is the model organism for
molecular genetic studies
Bodywall Muscle
developmental time
Hypoderm
John
Sulston
Neurons
Cuticular Cells
Pharynx
Intestine
Vulva
Gonad
Germ Cells
Muscle
Neuronal Cell Death Lineages
Brenner, S. (1973) ; Sulston, J. E., & Horvitz, H. R. (1977);
Sulston, J. E., et al. (1983); White, J. G., et al. (1982)
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Sydney
Brenner
Lecture V. Cell Birth & Death
H. Robert
Horvitz
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Programmed Cell Death of single identified
neurons can be followed in live worms
P11aap
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Lecture V. Cell Birth & Death
Sulston, J. E.,
& Horvitz, H. R. (1977)
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2 Classes of C. elegans Cell Death Mutants
(pro-survival genes + pro-apoptosis genes)
WT
(normal number of cells)
(pro-survival genes + pro-apoptosis genes)
Mutant class I
(fewer cells)
(pro-survival genes + pro-apoptosis genes)
Mutant class II
(extra cells)
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Genetic analysis of cell death genes
in C. elegans defines a genetic pathway
X
ced-3(lf)
X
ced-4(lf)
ced-9(lf)
ced-9(lf)
X
ced-9(lf)
ced-3(lf)
ced-4(lf)
X
excessive cell death (fewer cells)
animals die
as embryos
reduced cell death (extra cells)
reduced cell death (extra cells)
viable
viable
reduced cell death (extra cells)
reduced cell death (extra cells)
viable
viable
ced-4
ced-9
(pro-survival)
gene
ced-3
Cell
Death
(pro-apoptosis)
genes
Ellis, R. E., et al., (1991); Ellis, R. E., & Horvitz, H. R. (1991)
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t(14;18) Chromosomal Translocation Causes Human
B-Cell Leukemia by Overexpression of Bcl-2
Bcl-2
Chromosome 18
Ig Heavy Chain
Chromosome 14
Bcl-2
Chromosome 18
Stanley Korsmeyer
Ig Heavy Chain
Chromosome 14
Bcl-2
t(14;18) Chromosomal Translocation
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Lecture V. Cell Birth & Death
Cleary, M. L., et al., (1986);
Haldar, S., et al. (1990);
Korsmeyer, S. J. (1992);
Vaux, D. L., et al. (1988)
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The “core” Cell Death genes found in C. elegans are
conserved as multigene families in vertebrates
ced-9 / Bcl-2:
ced-4 / Apaf:
Bcl-2: B-Cell Leukemia.
• “Pro-survival” protein.
• Inhibits release of
cytochrome C from
mitochondria (vertebrates).
• Sequesters CED-4
from cytoplasm (worms). Xue, D., & Horvitz,
H. R. (1997)
Apaf: Apoptosis activity factor.
• “Adaptor” or “scaffold” protein.
• Aggregates inactive procaspase,
causing auto-activation by proximity.
• Requires cytochrome C, and ATP
for multimerization (vertebrates).
Yang, X., (1998)
ced-3 / Caspase:
Caspase: Cysteine
active-site, aspartate
cleavage-site, Protease.
• “Terminator” protein.
• Protease activity when activated by
proteolysis.
Xue, D., et al. (1996);Yuan, J. Y., &
Horvitz, H. R. (1990)
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Molecular Model for Apoptosis
mitochondria
Bcl-2
(ced-9)
---
single BH3
domain protein
Apaf
(egl-1)
(ced-4)
caspase
(ced-3)
(procaspase
recruitment)
-
--
---
(BH3 domains)
(*Catalysis of the
removal of
auto-inhibitory
caspase domain*)
Inactive
Procaspase
recruited
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Cytochrome C
Apaf aggregation
activated
caspase
(cascade)
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Death
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NGF is only one of multiple pathways to the “core”
death mechanism, through many single-BH3 proteins
Initiation of apoptosis by
extracellular ligands (FAS, TNF)
NGF
“Initiator”
caspase-8
Single BH3
domain protein
Single BH3
domain protein
*
*
*
*
BCL-2
*
Single BH3
domain protein
“Core” apoptotic components
Gross, A., et al., (1999)
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Apaf/Cytochrome C Aggregate into
a 7-Spoke Apoptosome Complex (“Wheel of Death”)
Single-particle
Electron Microscope
Analysis
WD-40
WD-40
Apaf
Cytochrome C
+procaspase-9 (x7?)
CARD
(caspase activation
and recruitment domain)
Apaf gene
procaspase-9
Acehan, D., et al. (2002)
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Single-BH3 domain molecules
integrate multiple signals that trigger apoptosis.
Mitochondria integrate “Pro-survival” and
“Pro-death”signals from a family of Bcl-2-like genes.
Pro-survival
Pro-death
(BH3)
BH3
Diptheria Toxin
(pore forming)
pA
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Bcl-xL
(Bcl-2 like)
(BH3)
“Pro-death” Single-BH3
domain proteins
complex with Bcl-2 to
release cytochrome C
from mitochondria
through “giant”
mitochondrial ionic
channels.
Lecture V. Cell Birth & Death
Schlesinger, P. H., et al.,
(2002), Fesik, (2000)
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Molecular Animation of Cell Death Mediated by
the FAS pathway
Berry, D. (2006) http://www.wehi.edu.au/education/wehi-tv/?page=2.
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What this Lecture was about
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Programmed cell death (apoptosis) is a physiological mechanism distinct
from necrotic cell death.
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Apoptosis occurs widely during normal development of the nervous
system.
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Isolation of specific molecules involved in promoting growth and survival –
“trophism,” e.g., Nerve Growth Factor (NGF).
•
What is the “death mechanism” that NGF (and other neruotrophins)
inhibit?
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Broader implications: controlled cell death in neuroembryology vs
uncontrolled cell growth of cancer.
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Gene homologies between organisms - humans and worms (nematodes)
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Molecular models for apoptosis
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How do trophic factors connect to this cell death pathway(s)?
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END
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