The Generation and Survival of Nerve

Cells

서울대학교 어린이병원 신경외과왕 규 창

Determination ofNeuron 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 neuron

s, negative regulation to cells nearby– Schwann cell vs. neuron population balance

Glial Differentiation in CNS oligodendrocyte

– platelet-derived growth factor (PDGF)– progenitor proliferation– produced by astrocyte– population balance control

astrocyte– ciliary neurotrophic factor (CNTF)

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.

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 acetylc

holine 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 transplantati

on or deletion in amphibian embryos– proliferation and differentiation of sensory neur

oblast (wrong) finding of neuronal death during normal dev

elopment

Neuronal Survival and Neuronal Target increased sensory neuronal death after limb

removal in chick embryos Half of the spinal cord motor neurons die du

ring the development in chick embryos. number of spinal cord motor neurons: influe

nced 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 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

p75NTR

similar affinity among neurotrphins promotes cell survival in the presence

of trk receptors promotes cell death in the absence of

trk receptors

Neurotrophic Factors 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 neurotr

ophic factors and receptors– 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 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): program

med cell death

Neurotrophin and Apoptosis

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 activa

tion of caspase: present