Ras Activity Oscillates in the Mouse Suprachiasmatic Nucleus and Modulates Circadian Clock Dynamics

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• 作者：Tsvetan Serchov ; Antje Jilg ; Christian T. Wolf ; Ina Radtke…
• 关键词：Ras ; SCN ; Photoentrainment ; Tau ; GSK3β ; ERK1 ; 2
• 刊名：Molecular Neurobiology
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：53
• 期：3
• 页码：1843-1855
• 全文大小：3,045 KB
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• 作者单位：Tsvetan Serchov (1) (2)
  Antje Jilg (3)
  Christian T. Wolf (1)
  Ina Radtke (1)
  Jörg H. Stehle (3)
  Rolf Heumann (1) (2)
  
  1. Department of Molecular Neurobiochemistry, Ruhr-University, 44780, Bochum, Germany
  2. International Graduate School of Neuroscience, Ruhr-University, 44780, Bochum, Germany
  3. Institute of Anatomy III, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany
  
• 刊物主题：Neurosciences; Neurobiology; Cell Biology; Neurology;
• 出版者：Springer US
• ISSN：1559-1182

文摘

Circadian rhythms, generated in the mouse suprachiasmatic nucleus (SCN), are synchronized to the environmental day–night changes by photic input. The activation of the extracellular signal-regulated kinases 1 and 2 (ERK1,2) and cAMP response element-binding protein (CREB)-mediated transcription play a critical role in this photoentrainment. The small GTPase Ras is one of the major upstream regulators of the ERK1,2/CREB pathway. In contrast to the well-described role of Ras in structural and functional synaptic plasticity in the adult mouse brain, the physiological regulation of Ras by photic sensory input is yet unknown. Here, we describe for the first time a circadian rhythm of Ras activity in the mouse SCN. Using synRas transgenic mice, expressing constitutively activated V12-Ha-Ras selectively in neurons, we demonstrate that enhanced Ras activation causes shortening of the circadian period length. We found upregulated expression and decreased inhibitory phosphorylation of the circadian period length modulator, glycogen synthase kinase-3 beta (GSK3β), in the SCN of synRas mice. Conversely, downregulation of Ras activity by blocking its function with an antibody in oscillating cell cultures reduced protein levels and increased phosphorylation of GSK3β and lengthened the period of BMAL1 promoter-driven luciferase activity. Furthermore, enhanced Ras activity in synRas mice resulted in a potentiation of light-induced phase delays at early subjective night, and increased photic induction of pERK1,2/pCREB and c-Fos. In contrast, at late subjective night, photic activation of Ras/ERK1,2/CREB in synRas mice was not sufficient to stimulate c-Fos protein expression and phase advance the clock. Taken together, our results demonstrate that Ras activity fine tunes the period length and modulates photoentrainment of the circadian clock.