The E3 ubiquitin ligase adaptor <i>Tango10</i> links the core circadian clock to neuropeptide and behavioral rhythms.

Abstract

Circadian transcriptional timekeepers in pacemaker neurons drive profound daily rhythms in sleep and wake. Here we reveal a molecular pathway that links core transcriptional oscillators to neuronal and behavioral rhythms. Using two independent genetic screens, we identified mutants of <i>Transport and Golgi organization 10</i> (<i>Tango10</i>) with poor behavioral rhythmicity. <i>Tango10</i> expression in pacemaker neurons expressing the neuropeptide PIGMENT-DISPERSING FACTOR (PDF) is required for robust rhythms. Loss of <i>Tango10</i> results in elevated PDF accumulation in nerve terminals even in mutants lacking a functional core clock. TANGO10 protein itself is rhythmically expressed in PDF terminals. Mass spectrometry of TANGO10 complexes reveals interactions with the E3 ubiquitin ligase CULLIN 3 (CUL3). CUL3 depletion phenocopies <i>Tango10</i> mutant effects on PDF even in the absence of the core clock gene <i>timeless</i> Patch clamp electrophysiology in <i>Tango10</i> mutant neurons demonstrates elevated spontaneous firing potentially due to reduced voltage-gated Shaker-like potassium currents. We propose that <i>Tango10/Cul3</i> transduces molecular oscillations from the core clock to neuropeptide release important for behavioral rhythms.