Circadian Period Integrates Network Information Through Activation of the BMP Signaling Pathway

: Circadian pacemaker neurons in the Drosophila brain gather network information through the highly conserved BMP signaling pathway to establish the daily period of locomotor behavior. Living organisms use biological clocks to maintain their internal temporal order and anticipate daily environmental changes. In Drosophila, circadian regulation of locomotor behavior is controlled by ∼150 neurons; among them, neurons expressing the PIGMENT DISPERSING FACTOR (PDF) set the period of locomotor behavior under free-running conditions. To date, it remains unclear how individual circadian clusters integrate their activity to assemble a distinctive behavioral output. Here we show that the BONE MORPHOGENETIC PROTEIN (BMP) signaling pathway plays a crucial role in setting the circadian period in PDF neurons in the adult brain. Acute deregulation of BMP signaling causes period lengthening through regulation of dClock transcription, providing evidence for a novel function of this pathway in the adult brain. We propose that coherence in the circadian network arises from integration in PDF neurons of both the pace of the cell-autonomous molecular clock and information derived from circadian-relevant neurons through release of BMP ligands.Author Summary: The circadian clock controls rhythms in behavior, physiology, and metabolism in all living organisms. The molecular components as well as the neuronal network required to keep this clock running have been identified in several species. In the Drosophila brain this neuronal network is represented by an ensemble of 150 neurons, and among them, those expressing the Pigment Dispersing Factor (PDF) neuropeptide encompass the “central oscillator”—also called master clock as it ensures 24-hour periods—of the fly brain. In this study we show that the widely conserved Bone Morphogenetic Protein (BMP) signaling pathway is present in PDF neurons, and upon adult-specific activation it lengthens the endogenous period of locomotor behavior. We find that period lengthening correlates with delayed accumulation of nuclear PERIOD, a core component of the molecular clock. We also identified a putative DNA binding motif for the BMP pathway nuclear components within the regulatory region of the Clock (Clk) promoter, another core component of the circadian machinery. Interestingly, upon BMP pathway activation endogenous CLK levels are downregulated, thus accounting for the lengthening of the endogenous period. We propose that the endogenous period is a network property commanded by PDF neurons that results from integration of information from both the autonomous molecular clock and the nonautonomous BMP signaling pathway.