1. The Generation and Survival of Nerve Cells
서울대학교 어린이병원 신경외과
왕 규 창

2. 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

3. Determination of Neuron vs. Glia
enhancer of split
basic helix-loop-helix protein
repress achaete-scute gene
achaete-scute gene
control level of delta
stochastic process: random selection

4. numb binds to the intracellular domain of notch
inhibits notch signaling
determinate lineage decision
selection by regulatory factors

5. 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

6. Neural Crest autonomic neurons glia 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

7. Glial Differentiation in CNS
oligodendrocyte
platelet-derived growth factor (PDGF)
progenitor proliferation
produced by astrocyte
population balance control
astrocyte
ciliary neurotrophic factor (CNTF)

8. Neuronal Fate in Cortex
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.

9. Germinal Matrix ventricular zone
early stage: expand population of progenitor cells
later: both neurons and progenitor cells
late stage: only neurons

10. Germinal Matrix symmetric cell division: progenitor cells
asymmetric cell division: neurons and progenitors
uneven distribution of numb protein
modulation of notch activity

11. 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

12. 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.

13. 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

14. 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

15. 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

16. Neurotrophins 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

17. p75NTR similar affinity among neurotrphins
promotes cell survival in the presence of trk receptors
promotes cell death in the absence of trk receptors

18. Neurotrophic Factors neurotrophin class interleukin 6 class
transforming growth factor beta class
fibroblast growth factor class
hepatocyte growth factor
sonic hedgehog

19. Neurotrophin antibody study
transgenic mouse: mutations in neurotrophic factors and receptors
NGF or trk A, NT3
absent sympathetic ganglia
partial depletion by one copy loss
Both factors are necessary.

20. 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

21. Neuronal Death Signal
p75
Fas

22. Apoptosis 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

23. 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

24. Neurotrophin and Apoptosis
neurotrophin binding
receptor activation
phosphorylation of proteins
promote bcl-2 like activities
inhibit caspase activity

25. Apoptosis DNA damage anoxia
bcl-2 and Apaf-1 independent activation of caspase: present