Circadian period integrates network information through activation of the BMP signaling pathway.

CERIANI, MF

Cancun

Congreso; I FALAN; 2012

Clocks employ self-sustained biochemical oscillators expressing at molecular, physiological and behavioral levels. In Drosophila, 150 neurons are implicated in circadian regulation of locomotor behavior; the small ventral lateral neurons (sLNvs) are clearly crucial. They express and release the neuropeptide Pigment Dispersing Factor (PDF) and set the period of locomotor behavior under free running conditions. To identify components involved in transmitting information relevant to network synchronization a screen was carried out through deregulation of gene expression in PDF+ cells. As a result a strain that causes period lengthening of daily activity rhythms was singled out affecting schnurri (shn), a nuclear component of the BMP signalling pathway. During development this pathway acts as a retrograde signal to define synaptic properties according stage-specific requirements. shn overexpression in the PDF circuit is necessary and sufficient to generate a 25.5h period of locomotor behavior, while downregulation of shn levels resulted in deconsolidated activity rhythms. Strikingly, adult-specific activation of BMP signalling in PDF+ cells is sufficient for period lengthening. To gain insight into the molecular mechanism PERIOD (PER) subcellular localization was analyzed. As predicted from the behavioral phenotype, PER nuclear entry was delayed upon shn overexpression, suggesting that pathway activation leads to downregulation of PER protein levels; in support of this possibility concomitant overexpression of PER (and CLOCK) rescued the long period phenotype. Additional experiments including transcriptional reporter lines supported the notion that shn overexpression (i.e., pathway activation) results in reduced CLOCK levels. We propose that controlled activation of the BMP pathway through the postsynaptic release of specific ligands is required to fine-tune circadian period in the adult brain. Thus, adult circadian period would integrate both, the pace of the cell autonomous molecular clock and information derived by other circadian relevant clusters to ensure coherence in the network.