Organisms from bacteria to humans use a circadian clock to control daily biochemical, physiological, and behavioral rhythms. This clock affects human physiology, and disruptions of normal clock function can cause health problems, including manic depression, and sleep disorders. We now have a firm understanding of the molecular oscillators that form the core of the circadian timing system. However, new data reveal that the circadian system is universally more complex than a single molecular feedback loop oscillator regulating all overt rhythmicity. Evidence now indicates that multiple circadian oscillators exist within single cells of microbial organisms and among the cells and tissues of multi-cellular organisms. We hypothesize that distinct multiple oscillators comprise the Neurospora crassa clock, and that these communicate with each other to generate a coordinated rhythmic program of cellular activities. We have identified two Neurospora mutant strains (Light Mutant 1 [LM1] and LM2) that display circadian rhythms in the absence of the FRQ/WC oscillator (FWO), previously considered to be the core of the fungal clock. These mutant strains uncover a novel circadian oscillator, called the LMO, which can function in cells that lack the FWO, but that is coupled to the FWO when the system is intact. A critical question that is relevant to the organization of all clocks, including the human clock, is: how do multiple oscillators communicate with each other to coordinately regulate circadian rhythms? To address this question, we will first determine the role of the LM1 and LM2 genes in the function of the LMO. Second, we will use genetic and physical methods to identify central components of the LMO. To test our hypothesis, we will determine if the LMO components physically interact with constituents of the FWO. In addition, LMO components will be inactivated in wild-type cells to determine if loss of the LMO affects the expression of key elements of the FWO and/or overt rhythmicity. To characterize LMO-specific outputs, we will use transcriptional profiling to identify genes that are rhythmically expressed in cells that have a functional LMO, but that lack the FWO. Lay Summary: These studies will provide the first molecular description of a second cellular oscillator, and will uncover the mechanisms by which circadian oscillators communicate with each other to coordinately control rhythmic processes. This in turn will facilitate new approaches for therapies for human conditions that result from circadian dysfunction.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Texas A&M University
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