Proceedings of the National Academy of Sciences of the United States of AmericaNov 20, 2021

The protein Tango10 connects the main body clock to daily cycles of brain signals and behavior

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Updated Mar 31, 2026

Abstract

Loss of the gene timeless results in elevated levels of the neuropeptide in nerve terminals.

Altered PDF levels are linked to poor behavioral rhythmicity in mutants of timeless.
The protein is rhythmically expressed in PDF terminals and is associated with the E3 ubiquitin ligase CUL3.
Depletion of CUL3 produces similar effects to timeless mutants on PDF levels, even without the core clock gene.
Mutant neurons show increased spontaneous firing, likely due to reduced potassium currents.

Simplified

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() with poor behavioral rhythmicity.expression in pacemaker neurons expressing the neuropeptide PIGMENT-DISPERSING FACTOR () is required for robust rhythms. Loss ofresults in elevated PDF accumulation in nerve terminals even in mutants lacking a functional core clock. 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 phenocopiesmutant effects on PDF even in the absence of the core clock genePatch clamp electrophysiology inmutant neurons demonstrates elevated spontaneous firing potentially due to reduced voltage-gated Shaker-like potassium currents. We propose thattransduces molecular oscillations from the core clock to neuropeptide release important for behavioral rhythms. Transport and Golgi organization 10Tango10Tango10Tango10Tango10timeless Tango10Tango10/Cul3

Key numbers

∼95%

Rhythmic Power Reduction

Loss of leads to a dramatic reduction in rhythmic power.

2×

Level Increase

mutants show elevated levels compared to wild-type.

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The protein Tango10 connects the main body clock to daily cycles of brain signals and behavior

Abstract

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