■演者：Gregor Eichele 博士
Genes & Behavior Department, Max Planck Institute of Biophysical Chemistry, Professor
■演題：The Molecular- and Organismal-Levels of Regulation of the Mammalian Circadian Clock
Nearly all tissues express a group of core clock proteins that compose transcriptional/translational feedback loops (TTLs) generating both, a self-sustained 24-hour rhythm and a rhythmic expression of clock
controlled genes (CCGs). These CCGs then mediate the wide spectrum cellular and organismal circadian processes such as adrenal cortisol secretion and the sleep wake cycle. Ensuring that the many tissue-specific circadian clocks (aka “peripheral clocks”) are synchronized is the mission of the master clock of the suprachiasmatic nucleus (SCN).
The main TTL consists of the transcription factors CLOCK and BMAL1 that activate transcription of Per and Cry genes both of which encode repressor proteins that inhibit CLOCK and BMAL1 activity (negative feedback). In the course of the late day, PER and CRY are degraded which allows for a new round of CLOCK/BMAL1-dependent transcriptional activation and rings in a new day. The molecular mechanism by which PER and CRY exert their inhibitory role is elusive. Using genomic and proteomic screening approaches, we have begun to identify PER and CRY-interacting proteins and are now focusing on those that are candidates for mediating the negative feedback. We will discuss the mechanism of one particular CRY-interacting protein that we have discovered and that seems to be a necessary and sufficient component of the negative feedback mechanism of the mammalian circadian clock.
The chief evidence for a pivotal role of the SCN in coordinating the rhythm of the body’s diverse clocks rests on SCN ablation experiments that lead to a complete loss of the physiological and molecular rhythms of all peripheral clocks. Inevitably, ablation is accompanied by a scission of the SCN afferents and efferents. To circumvent this major shortcoming, we have designed SCN specific Cre recombinase driver lines that allowed us to genetically ablate the core clock in the SCN. We will show how this impinges on the physiological and molecular rhythm of peripheral clocks and discuss how these results reshape some of our views on the mammalian circadian clock.
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