NE102 Lecture Notes 3

Question how does ngf induce neural differentiation

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QUESTION: How does NGF induce neural differentiation of PC12 cells? Effect of a Dominant Inhibitory Ha- ras  Mutation on Neuronal Differentiation of PC12  Cells paper KEY OBSERVATION: Expression of dominant-negative Ras blocks NGF-induced  differentiation QUESTION: Does Ras induce differentiation through the Raf/MEK/ERK pathway? Expression of dominant-negative Raf, MEK, or ERK blocks NGF-induced differentiation BASED ON THESE EXPERIMENTS: Ras/Raf/MEK/ERK signaling is  necessary  for NGF-induced differentiation  QUESTION: IS Ras/Raf/MEK/ERK signaling sufficient for neuronal differentiation? (1) Inhibition of ERK signaling blocks differentiation: Introducing dominant-negative Ras, Raf, MEK, or ERK Drugs that block ERK activation (2) Activation of ERK signaling (without NGF) is sufficient to induce differentiation Introducing constitutively active Ras, Raf, MEK, or ERK
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Integrating Concepts through PC12 Differentiation 18:04 Problem with this simplistic model when you use other growth factors. Epidermal Growth Factor (EGF) induces  cell proliferation  and not cell differentiation.  Inhibit EGF, MAP kinase pathway is inhibited, cell proliferation does not occur. Inhibit NGF, MAP kinase pathway is inhibited, cell differentiation does not occur.  NEW CHALLENGE: How can EGF and NGF stimulate different cell behavrios through  the same signaling pathway? NGF induces sustained MEK/ERK signaling (compared to EGF)  NEW HYPOTHESIS: NGF induces neuronal differentiation via sustained ERK signaling NOW ONGOING HYPOTHESIS: NGF Induces neuronal differentiation via sustained  ERK signaling HOW? Hypothesis #1: Transient and sustained ERK signaling activate distinct transcription  programs EGF and NGF both induce expression of 100’s of genes…most of them the same Hypothesis #2: Sustained ERK signaling causes sustained expression of a subset of  genes that initiate neuronal differentiation Examined and compared gene expression at 2 & 4 hours after EGF and NGF treatment 
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NE101 Recap – “Integrative Biology” 18:04 Levels of biological analysis Ecosystem level, community level, population level, organism level, organ system level,  organ level, tissue level, cellular level, molecular level Today’s theme: Cell and molecular concepts are important at all levels of biological  analysis.  Today’s goals: To “open three critical black boxes” from NE101 1. Genes and genetic variation 2. Developing neurons 3. Patterning BLACK BOX #1: GENES AND GENETIC VARIATION Evolution Variation Heritability  Alleles  are DNA sequence variants of the same chromosomal position (locus) If the frequencies of these sequence variants changes in the population over time,  evolution is occurring. 
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