BIOPHYSICAL THEORY AND MODELING |
A Molecular Model for Intercellular Synchronization in the Mammalian Circadian Clock
Tsz-Leung To 1, Michael A Henson 2*, Erik D Herzog 3 and Francis J Doyle III 4
1 Massachusetts Institute of Technology
2 University of Massachusetts Amherst
3 Washington University
4 University of California, Santa Barbara
* To whom correspondence should be addressed. E-mail: henson{at}ecs.umass.edu.
Submitted on July 27, 2006
Revised on September 17, 2006
Accepted on 22 January 2007
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Abstract |
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The mechanisms and consequences of synchrony among heterogeneous oscillators are poorly understood in biological systems. We present a multicellular, molecular model of the mammalian circadian clock that incorporates recent data implicating the neurotransmitter vasoactive intestinal polypeptide (VIP) as the key synchronizing agent. The model postulates that synchrony arises among circadian neurons because they release VIP rhythmically on a daily basis and in response to ambient light. Two basic cell types, intrinsically rhythmic pacemakers and damped oscillators, are assumed to arise from a distribution of Period (Per) gene transcription rates. Postsynaptic neurons show time-of-day dependent responses to VIP binding through a signaling cascade that activates Per mRNA transcription. The heterogeneous cell ensemble model self-synchronizes, entrains to ambient light-dark cycles, and desynchronizes in constant bright light or upon removal of VIP signaling. The degree of synchronicity observed depends on cell-specific features (e.g. mean and variability of parameters within the rhythm generating loop), in addition to the more commonly studied effect of intercellular coupling strength. These simulations closely replicate experimental data and predict that heterogeneous oscillations (e.g. sustained, damped and arrhythmic) arise from small differences in the molecular parameters between cells, that damped oscillators participate in entrainment and synchrony of the ensemble of cells, and that constant light desynchronizes oscillators by maximizing VIP release.
Key Words:
Circadian rhythm, Gene regulation, Intercellular signaling, Multicellular model, Synchronization
