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

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 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 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

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 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 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 neurotrophic 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): programmed 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 activation of caspase: present