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.

Signaling pathways regulating Homer1a expression: implications for antidepressant therapy

“…Interestingly, we have demonstrated light-induced regulation of the Ras signaling cascade (Serchov and Heumann, 2006;Serchov et al, 2015b). In order to study the role of Ras, we have generated a transgenic mouse model expressing constitutively activated Ras selectively in neurons (synRas mice) (Heumann et al, 2000).…”

The small G protein RAS2 is involved in the metabolic compensation of the circadian clock in the circadian model Neurospora crassa

“…Both experimental data and bioinformatic analysis suggest that oncogenic RAS proteins are involved in the deregulation of the circadian clock in cancer cells (53). Finally, it was recently shown that RASsignaling affects the circadian clock in the suprachiasmatic nucleus of mice acting, at least partially, via ERK and glycogen synthase kinase (GSK), and thereby fine-tunes the circadian period (54). Our goal in this study was to investigate whether RAS2 is involved in the metabolic compensation of the circadian clock of Neurospora crassa.…”

A Ras GTPase associated protein is involved in the phototropic and circadian photobiology responses in fungi

“…A potential mammalian link is the role of the Ras family member, Dexras1, in the light input into the circadian clock in mice46. Other studies continue to implicate an essential role for Ras signaling in circadian rhythms in animals474849.…”