This two-kinase phosphorylation cascade is anatomically restricted to the eight master pacemaker neurons, distinguishing the regulatory mechanism of the molecular clock within these neurons from the other clocks that cooperate to govern behavioral rhythmicity.Ĭircadian behavior is the anticipation and response to cyclic environmental changes, such as light/dark cycles, that recur with a period of ~24 h. Mutations that block the hierarchical phosphorylation of Timeless in vitro, also delay nuclear accumulation in both tissue culture and in vivo, and predictably change rhythmic behavior. GSK-3/SGG binds and phosphorylates Period-bound Timeless, triggering a CK2-mediated phosphorylation cascade. Combining biochemical and genetic techniques in Drosophila, we identify a phosphorylation program native to the master pacemaker neurons that regulates the timing of nuclear accumulation of the Period/Timeless repressor complex.
Although the principal components of the clock are present in all circadian neurons, different neuronal clusters have varying effects on rhythmic behavior, suggesting that the clocks they house are differently regulated. The molecular clock relies on a delayed negative feedback loop of transcriptional regulation to generate oscillating gene expression.
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