mechanismandlevels

mechanismandlevels - 11/21/11 Mechanism and Levels of...

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11/21/11 1 Mechanism and Levels of Organization: Recomposing and Situating Circadian Clocks The Success of Decomposition Moving beyond per , researchers in the 1990s and early 2000s identified many clock components. Focusing just on mammals, these include: – Multiple forms of Per in mammals – Two form of cryptochrome dimerization partner of Per – Melanopsin entrainment Clock activator of Per Bmal1 activator of Per – CASEIN KINASE 1 ε (and other kinases) degradation Ror α and Rev-erb α activator and inhibitor of Bmal1 – Many chaperones – Various acetylases/methylases – etc., etc., etc. Putting the Mechanism Back Together A pile of separated parts won’t produce the phenomenon To understand how they contribute to the phenomenon, need to recompose the mechanism – Very hard to do so in reality (but new promise in synthetic biology) – Much of the focus is on recomposing a mechanism conceptually • Identifying how the parts are related and affect each other
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11/21/11 2 First Step: Transcription/ Translation Feedback Loop The proposal of the transcription/translation feedback loop and its linking to entrainment is a first step of recomposition The Continuing Challenge of Recomposing the Intracellular Clock Genome-wide screen using small interfering RNA (siRNA) has identified more than 200 genes that affect clock period and amplitude Includes genes from four signaling pathways – Insulin pathway – Cell cycle – Hedgehog signaling – Folic acid biosynthesis The clock mechanism increasingly appears to be highly intertwined with the rest of the cell 5 From Zhang and Kay, 2010 Recomposing Beyond the Individual Cell We saw how researchers first localized circadian rhythms in mammals in the suprachiasmatic nucleus and then focused on finding the responsible mechanism within individual cells of the SCN But the SCN could only provide time information to the rest of the organisms if it is properly hooked up to it Before we get to that, there is the question of how the individual neurons are connected in the SCN – Naïve hypothesis: The neurons in the SCN are all doing the same thing Dibner et al., 2010
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11/21/11 3 Individual SCN Neurons Oscillate, But Not in Synchrony Welsh et al. (1995) studied SCN neurons in a dissociated culture system – Despite l abundant functional synapses, z neurons exhibited rhythms of widely different phases and periods • the four cells shown spike far out of phase with each other – Some exhibit peak spiking while others are exhibiting minimal activity • Periods range from 21.25 to 26.25 hours, with SD = 1.25 hours From Welsh et al., 1995 Cell Autonomous Oscillators By recording from two individual neurons (blue and red hash marks) when their firing rate exceeds their daily mean, Welsh clearly showed that they had different periods Inhibiting action potentials with
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This note was uploaded on 12/12/2011 for the course PHIL 147 taught by Professor Bechtel,w during the Fall '08 term at UCSD.

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mechanismandlevels - 11/21/11 Mechanism and Levels of...

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