title: Ras Activity Oscillates in the Mouse Suprachiasmatic Nucleus and Modulates Circadian Clock Dynamics.
abstract: 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.
authors.affiliation: Department of Molecular Neurobiochemistry, Ruhr-University, 44780, Bochum, Germany.|International Graduate School of Neuroscience, Ruhr-University, 44780, Bochum, Germany.
authors.forename: Tsvetan
authors.initials: T
authors.lastname: Serchov
authors.affiliation: Institute of Anatomy III, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Jilg
authors.affiliation: Department of Molecular Neurobiochemistry, Ruhr-University, 44780, Bochum, Germany.
authors.forename: Christian T
authors.initials: CT
authors.lastname: Wolf
authors.affiliation: Department of Molecular Neurobiochemistry, Ruhr-University, 44780, Bochum, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Radtke
authors.affiliation: Institute of Anatomy III, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.
authors.forename: Jörg H
authors.initials: JH
authors.lastname: Stehle
authors.affiliation: Department of Molecular Neurobiochemistry, Ruhr-University, 44780, Bochum, Germany. rolf.heumann@rub.de.|International Graduate School of Neuroscience, Ruhr-University, 44780, Bochum, Germany. rolf.heumann@rub.de.
authors.forename: Rolf
authors.initials: R
authors.lastname: Heumann
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics; D000818:Animals; D057906:Circadian Clocks / Q000528:radiation effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D011905:Genes, ras; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006801:Humans; D008027:Light; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000528:radiation effects; D010766:Phosphorylation / Q000528:radiation effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D015398:Signal Transduction; D013493:Suprachiasmatic Nucleus / Q000378:metabolism* / Q000528:radiation effects
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D016760:Proto-Oncogene Proteins c-fos; D000071679:Glycogen Synthase Kinase 3 beta; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: ERK1,2; GSK3β; Photoentrainment; Ras; SCN; Tau