Interlocked feedback loop contribute to the robustness of the Neurospora circadian clock

Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9040, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 07/2001; 98(13). DOI: 10.1073/pnas.121170298
Source: PubMed Central


Interlocked feedback loops may represent a common feature among the regulatory systems controlling circadian rhythms. The Neurospora circadian feedback loops involve white collar-1 (wc-1), wc-2, and frequency (frq) genes. We show that WC-1 and WC-2 proteins activate the transcription of frq gene, whereas FRQ protein plays dual roles: repressing its own transcription, probably by interacting with the WC-1/WC-2 complex, and activating the expression of both WC proteins. Thus, they form two interlocked feedback loops: one negative and one positive. We establish the physiological significance of the interlocked positive feedback loops by showing that the levels of WC-1 and WC-2 determine the robustness and stability of the clock. Our data demonstrate that with WC-1 being the limiting factor in the WC-1/WC-2 complex, the greater the levels of WC-1 and WC-2, the higher the level of the FRQ oscillation and the more robust the overt rhythms. Our data also show that, despite considerable changes in the levels of WC-1, WC-2, and FRQ, the period of the clock has been limited to a small range, suggesting that the interlocked circadian feedback loops are also important for determining the circadian period length of the clock.

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    • "For example, the circadian clock network of the model fungal species Neurospora crassa is built around a central negative feedback loop augmented by an interlocking positive loop (Baker et al., 2012). It has been shown experimentally that the positive loop reduces the variability in the free-running period of the clock (Cheng et al., 2001; Smolen et al., 2001), thereby promoting its robust synchronization to the external LD cycle. Subsequent ODE modeling of the Neurospora clock has demonstrated that this interlocked feedback structure also imparts the flexibility necessary to tune the dependence of oscillator phase on both day length (Akman et al., 2008) and ambient temperature (Akman et al., 2010b), yielding a potentially generic mechanism by which temperature compensation can be achieved in a clock network (Akman et al., 2010b). "
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