Transcript The Generation and Survival of Nerve Cells

The Generation and
Survival of Nerve Cells
서울대학교 어린이병원 신경외과
왕규창
Determination of
Neuron vs. Glia
 proneural region of Drosophila
 notch signaling
– low level: neuron
– high level: glia
 suppressor of hairless
– transcription factor
– basic helix-loop-helix protein
– encoded by proneural genes
Determination of
Neuron vs. Glia
 enhancer of split
– basic helix-loop-helix protein
– repress achaete-scute gene
 achaete-scute gene
– basic helix-loop-helix protein
– control level of delta
 stochastic process: random selection
numb
 binds to the intracellular domain of notch
 inhibits notch signaling
 determinate lineage decision
– selection by regulatory factors
neurogenin, neuroD
 basic helix-loop-helix gene
 appears before delta in the three
proneural stripes (Xenopus)
 induces additional neurons
 neurons, not restricted to the neural
plate stripes
Neural Crest
 autonomic neurons
– bone morphogenetic proteins
– mash-1: basic helix-loop-helix protein
 glia
– glial growth factor (GGF)
– encoded by neuregulin gene
– expressed on the surface of autonomic
neurons, negative regulation to cells nearby
– Schwann cell vs. neuron population balance
Glial Differentiation in CNS
 oligodendrocyte
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platelet-derived growth factor (PDGF)
progenitor proliferation
produced by astrocyte
population balance control
 astrocyte
– ciliary neurotrophic factor (CNTF)
Neuronal Fate in Cortex
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from ventricular zone
inside-first, outside-last
migration
transplantation experiment
– young cells in S phase: environmental signal
– young cells passed S phase: cell’s own fate
– Later stage cells do not acquire fate of young
neurons.
Germinal Matrix
 ventricular zone
 early stage: expand population of
progenitor cells
 later: both neurons and progenitor cells
 late stage: only neurons
Germinal Matrix
 symmetric cell division: progenitor cells
 asymmetric cell division: neurons and
progenitors
– uneven distribution of numb protein
– modulation of notch activity
Neurotransmitter Phenotype
 controlled by signals from the neuronal
target
 exocrine sweat glands in the foot pad
– changes from norepinephrine to acetylcholine
system once axons contact this sweat glands
– leukemia inhibitory factor (LIF) and CNTF
– transplantation experiment in rat: maintain
acetylcholine activity
Neurotransmitter Phenotype
in the Brain
 exocrine sweat gland type: not universal
 For many neurons in the brain, the
choice of neurotransmitter appears to be
part of the cells’ intrinsic neurogenic
program.
Neuronal Survival and
Neuronal Target
 sensory neurons and limb bud
transplantation or deletion in amphibian
embryos
– proliferation and differentiation of sensory
neuroblast (wrong)
 finding of neuronal death during normal
development
Neuronal Survival and
Neuronal Target
 increased sensory neuronal death after
limb removal in chick embryos
 Half of the spinal cord motor neurons die
during the development in chick embryos.
 number of spinal cord motor neurons:
influenced by limb transplantation and
removal
 neurotrophic factor hypothesis
Neuronal Survival and
Neuronal Target
 activity of the target cell
– curare and stimulation experiment
 neurotrophic factor: normally limited
amount
 electrical activity of neurons:
necessary for responses to the
trophic factors
Neurotrophins
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nerve growth factor (NGF)
brain-derived neurotrophic factor (BDNF)
neurotrophin 3 (NT3)
neurotrophin 4/5 (NT4,5)
receptors: trkA, trkB, and trkC
– membrane-spanning tyrosine kinases
– needs dimerization
 p75NTR
NTR
p75
 similar affinity among neurotrphins
 promotes cell survival in the
presence of trk receptors
 promotes cell death in the absence
of trk receptors
Neurotrophic Factors
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neurotrophin class
interleukin 6 class
transforming growth factor beta class
fibroblast growth factor class
hepatocyte growth factor
sonic hedgehog
Neurotrophin
 antibody study
 transgenic mouse: mutations in
neurotrophic factors and receptors
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NGF or trk A, NT3
absent sympathetic ganglia
partial depletion by one copy loss
Both factors are necessary.
Role of Neurotrophin
in CNS
 normal number of motor neurons in
transgenic mice
 complex in CNS
 other neurotrophic factors (+)
– TGF beta, interleukin 6 like proteins,
hepatocyte growth factors
– lack of glial-derived neurotrophic factor:
20-30% neuronal loss
Neuronal Death Signal
 p75
 Fas
Apoptosis
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cell shrinkage
condensation of chromatin
cellular fragmentation
phagocytosis of cellular remnant
necrosis
– rapid lysis of cellular membrane without
activation of the endogenous cell death
program
Apoptosis
 needs protein and RNA synthesis
 neurotrophins: suppress an endogenous
cell death program
 endogenous death program research
– C. elegans
– 15% of cells (most of them are neurons):
programmed cell death
Neurotrophin and
Apoptosis
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neurotrophin binding
receptor activation
phosphorylation of proteins
promote bcl-2 like activities
inhibit caspase activity
Apoptosis
 DNA damage
 anoxia
 bcl-2 and Apaf-1 independent
activation of caspase: present