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The Journal of Neuroscience, December 13, 2006, 26(50):12984-12995; doi:10.1523/JNEUROSCI.4253-06.2006

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Behavioral/Systems/Cognitive
The Molecular Gatekeeper Dexras1 Sculpts the Photic Responsiveness of the Mammalian Circadian Clock

Hai-Ying M. Cheng,¹ Heather Dziema,¹ Joseph Papp,¹ Daniel P. Mathur,¹ Margaret Koletar,² Martin R. Ralph,² Josef M. Penninger,³ and Karl Obrietan¹

¹Department of Neuroscience, The Ohio State University, Columbus, Ohio 43210, ²Centre for Biological Timing and Cognition and Department of Psychology, University of Toronto, Toronto, Ontario, Canada M5S 3G3, and ³Institute of Molecular Biotechnology of the Austrian Academy of Sciences, A-1030 Vienna, Austria

Correspondence should be addressed to Hai-Ying M. Cheng, Department of Neuroscience, The Ohio State University, Graves Hall, Room 4118, 333 West 10th Avenue, Columbus, OH 43210. Email: hymcheng{at}yahoo.ca

The mammalian master clock, located in the suprachiasmatic nucleus (SCN), is exquisitely sensitive to photic timing cues, but the key molecular events that sculpt both the phasing and magnitude of responsiveness are not understood. Here, we show that the Ras-like G-protein Dexras1 is a critical factor in these processes. Dexras1-deficient mice (dexras1^–/–) exhibit a restructured nighttime phase response curve and a loss of gating to photic resetting during the day. Dexras1 affects the photic sensitivity by repressing or activating time-of-day-specific signaling pathways that regulate extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK). During the late night, Dexras1 limits the capacity of pituitary adenylate cyclase (PAC) activating peptide (PACAP)/PAC1 to affect ERK/MAPK, and in the early night, light-induced phase delays, which are mediated predominantly by NMDA receptors, are reduced as reported previously. Daytime photic phase advances are mediated by a novel signaling pathway that does not affect the SCN core but rather stimulates ERK/MAPK in the SCN shell and triggers downregulation of clock protein expression.

Key words: Dexras1; MAPK; circadian; photic; entrainment; PACAP; suprachiasmatic

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Received June 4, 2006; revised Oct. 31, 2006; accepted Nov. 6, 2006.

Correspondence should be addressed to Hai-Ying M. Cheng, Department of Neuroscience, The Ohio State University, Graves Hall, Room 4118, 333 West 10th Avenue, Columbus, OH 43210. Email: hymcheng{at}yahoo.ca

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				H.-Y. M. Cheng, M. Alvarez-Saavedra, H. Dziema, Y. S. Choi, A. Li, and K. Obrietan Segregation of expression of mPeriod gene homologs in neurons and glia: possible divergent roles of mPeriod1 and mPeriod2 in the brain Hum. Mol. Genet., August 15, 2009; 18(16): 3110 - 3124. [Abstract] [Full Text] [PDF]

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