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Simulating Dark Expressions and Interactions of frq and wc-1 in the Neurospora Circadian Clock

Christian I. Hong ^* , Ingunn W. Jolma ^*, Jennifer J. Loros , Jay C. Dunlap   and Peter Ruoff ^*

^* Department of Mathematics and Natural Science, University of Stavanger, N-4036 Stavanger, Norway; and Departments of Genetics and Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755

Correspondence: Address reprint requests to Peter Ruoff, University of Stavanger, Faculty of Science and Technology, Dept. of Mathematics and Natural Science, N-4036 Stavanger, Norway. Tel.: 47-5183-1887; Fax: 47-5183-1750; E-mail: peter.ruoff{at}uis.no.

Circadian rhythms are considered to play an essential part in the adaptation of organisms to their environments. The occurrence of circadian oscillations appears to be based on the presence of transcriptional-translational negative feedback loops. In Neurospora crassa, the protein FREQUENCY (FRQ) is part of such a negative feedback loop apparently by a direct interaction with its transcription factor WHITE COLLAR-1 (WC-1). Based on the observation that nuclear FRQ levels are significantly lower than nuclear WC-1 levels, it was suggested that FRQ would act more like a catalyst in inhibiting WC-1 rather than binding to WC-1 and making an inactive FRQ:WC-1 complex. Intrigued by this hypothesis, we constructed a model for the Neurospora circadian clock, which includes expression of the frq and the wc-1 genes and their possible interactions. The model suggests that even small amounts of nuclear FRQ-protein are capable of inhibiting frq transcription in a rhythmic manner by binding to WC-1 and promoting its degradation. Our model predicts the importance of a FRQ dependent degradation of WC-1 in closing the negative feedback loop. The model shows good agreement with experimental levels in nuclear and cytosolic FRQ and WC-1, their phase relationships, and several clock mutant phenotypes.