Abstract
Author SummaryCircadian clocks provide a mechanism for predicting and adapting behavioral and physiological processes to 24-hour rhythms in the environment. In animal nervous systems, cell-autonomous molecular oscillators are coupled via neural networks that control daily patterns of activity. A major neuropeptide synchronizing neural oscillators in the Drosophila clock network is PIGMENT DISPERSING FACTOR (PDF). Here we identify a fork in the processing of the PDF signal in circadian neurons to independently reset the molecular clock and regulate neuronal activity. We show that the cAMP-activated protein kinase A (PKA) in circadian neurons is necessary and sufficient for many PDF-dependent behaviors. In addition, we find that a PDF>PDF receptor>PKA pathway targets the clock component TIMELESS to control molecular oscillators, and that this process may be influenced by rhythmic expression of PKA. We show that this pathway splits at the level of cAMP generation, with PDF and cAMP acutely increasing the activity of clock neurons in a PKA-independent manner. Thus, PDF operates via dual signaling pathways: one via PKA to reset clocks and the other via cAMP to acutely control activity. These results have broad implications given the conserved involvement of neuropeptide signaling in synchronizing clocks in circadian neural networks.
Highlights
Circadian clocks endow organisms with the ability to predict and respond adaptively to daily changes in the environment
We tested the function of the cAMP-dependent protein kinase A (PKA) in clock neurondriven behavior. cAMP is the canonical activator of PKA activity. cAMP binds the PKA regulatory (R) subunit releasing the catalytic (C) subunit to phosphorylate substrates
In addition to expression in the PIGMENT DISPERSING FACTOR (PDF) clock neurons [5], we examined cwo-G4 driven nuclear green fluorescent protein (GFP) expression in pacemaker neurons using PER co-labeling
Summary
Circadian clocks endow organisms with the ability to predict and respond adaptively to daily changes in the environment. In many taxa, these clocks consist of cell-autonomous molecular feedback loops, producing ,24-hour oscillations at the mRNA and protein levels. In Drosophila, the molecular circadian clock consists of a set of interlocked transcriptional feedback loops in which the basic helixloop-helix per-arnt-sim (bHLH-PAS) domain transcription factor CLOCK (CLK) forms a heterodimer with CYCLE (CYC) and binds E-boxes in the promoter regions of period (per), timeless (tim), vrille (vri), Par-domain protein 1e (Pdp1e) and clockwork orange (cwo), promoting their transcription (reviewed in [1]). In contrast to transcriptional regulators, significant oscillations have not been described for these posttranslational regulators with the exception of the PP2A subunits tws and wdb [26]
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