Bio 3411

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Lecture V. Cell Birth and Death

• Bio 3411
• Wednesday
• September 9, 2009

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• T. Woolsey
• 3802 North Building
• 362-3601
• woolseyt_at_medicine.wustl.edu

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Readings

• NEUROSCIENCE 4th ed, pp 596-609
• References posted
• Abbott, A. (2009). Neuroscience One hundred
  years of Rita. Nature, 458(7238), 564-567.
• Berry, D. (2006). Apoptosis and signal
  transduction. http//www.wehi.edu.au/education/weh
  i-tv/?page2.
• Cohen, S. (1987). Autobiography.
  http//nobelprize.org/nobel_prizes/medicine/laurea
  tes/1986/cohen-autobio.html
• Hengartner, M. O. (2000). The biochemistry of
  apoptosis. Nature, 407(6805), 770-776.
• Hollyday, M. (2001). Viktor Hamburger
  (1900-2001) A rememberance. Developmental
  Biology, 236(1), 1-2.
• Raff, M. (1998). Cell suicide for beginners.
  Nature, 396(6707), 119-122.
• ______________________
• (pdfs on course website http//artsci.wustl.edu
  /sdanker/index.html)

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Cited A

• 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(1418)
  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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Cited B

• 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

• 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

• 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-ß) 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
from Greekapo meaning separationptosis
for falling off
Kerr, J. F., et al.,(1972)
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Types of Cell Death

• Not Self-Initiated
• Not Stereotypic
• Can Be Slow
• Messy
• (injury can spread)

Necrosis (Provoked)

• Cell-Autonomous
• Stereotypic
• Rapid
• Clean
• (dead cells eaten)

Apoptosis (Programmed)
Ellis, R. E., et al., (1991)
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Removing a neurons targets, leads to its death
Hamburger, V. (1958,1977)
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Neuronal death is central for normal NS
development
Hamburger, (1975) Landmesser Pilar,
(1974) Cowan Wenger, (1967)
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Neuron survival correlates with target innervation
Target Muscles
Motor neurons
Axon Outgrowth
Development Progresses
Target Innervation
Neuronal Loss
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Target innervation determines which neurons
survive
Development Progresses
More targets (more neurons)
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
Hollyday, M. (2001) Abbott, A. (2009). Cohen,
S. (1987)
Levi-Montalcini, et al. (1954) Cohen, S., et al.
(1954)
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NGF is the founding member of a large gene
family of Neurotrophins (NTs), distantly related
to insulin
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)
Apoptosis pathway
Multiple Signaling Pathways Via kinases and
scaffolding proteins
(PIK3/AKT kinase)
(PLC/PKC kinase)
(Ras/MAP kinase)
Intracellular Ca2 release, modulation of ion
channels
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C. elegans is the model organism for molecular
genetic studies
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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Programmed Cell Death of single
identified neurons can be followed in live worms
Sulston, J. E., Horvitz, H. R. (1977)
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2 Classes of C. elegans Cell Death Mutants
WT
Mutant class I
Mutant class II
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Genetic analysis of cell death genes in C.
elegans defines a genetic pathway
Ellis, R. E., et al., (1991) Ellis, R. E.,
Horvitz, H. R. (1991)
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t(1418) Chromosomal Translocation Causes Human
B-Cell Leukemia by Overexpression of Bcl-2
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
Xue, D., Horvitz, H. R. (1997)
Yang, X., (1998)
Xue, D., et al. (1996)Yuan, J. Y., Horvitz, H.
R. (1990)
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Molecular Model for Apoptosis
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NGF is only one of multiple pathways to the
core death mechanism, through many single-BH3
proteins
Gross, A., et al., (1999)
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Apaf/Cytochrome C Aggregate into a 7-Spoke
Apoptosome Complex (Wheel of Death)
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-deathsignals from a family of Bcl-2-like
genes.
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/?page2.
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What this Lecture was about

• Programmed cell death (apoptosis) is a
  physiological mechanism distinct from necrotic
  cell death. 
• Apoptosis occurs widely during normal development
  of the nervous system. 
• 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?  
• Broader implications controlled cell death in
  neuroembryology vs uncontrolled cell growth of
  cancer.
• Gene homologies between organisms - humans and
  worms (nematodes) 
• Molecular models for apoptosis 
• How do trophic factors connect to this cell death
  pathway(s)?

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END