Vasoactive intestinal peptide controls the suprachiasmatic circadian clock network via ERK1/2 and DUSP4 signalling

Nat Commun. 2019 Feb 1;10(1):542. doi: 10.1038/s41467-019-08427-3.

Abstract

The suprachiasmatic nucleus (SCN) co-ordinates circadian behaviour and physiology in mammals. Its cell-autonomous circadian oscillations pivot around a well characterised transcriptional/translational feedback loop (TTFL), whilst the SCN circuit as a whole is synchronised to solar time by its retinorecipient cells that express and release vasoactive intestinal peptide (VIP). The cell-autonomous and circuit-level mechanisms whereby VIP synchronises the SCN are poorly understood. We show that SCN slices in organotypic culture demonstrate rapid and sustained circuit-level circadian responses to VIP that are mediated at a cell-autonomous level. This is accompanied by changes across a broad transcriptional network and by significant VIP-directed plasticity in the internal phasing of the cell-autonomous TTFL. Signalling via ERK1/2 and tuning by its negative regulator DUSP4 are critical elements of the VIP-directed circadian re-programming. In summary, we provide detailed mechanistic insight into VIP signal transduction in the SCN at the level of genes, cells and neural circuit.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CRISPR-Cas Systems
  • Circadian Clocks / drug effects*
  • Circadian Clocks / genetics
  • Circadian Clocks / radiation effects
  • Cyclic AMP / metabolism
  • Feedback, Physiological / drug effects
  • Feedback, Physiological / radiation effects
  • Gene Regulatory Networks / drug effects
  • Gene Regulatory Networks / radiation effects
  • Light
  • MAP Kinase Signaling System / drug effects*
  • MAP Kinase Signaling System / radiation effects
  • Mice, Knockout
  • Protein Biosynthesis / drug effects
  • Protein Biosynthesis / radiation effects
  • Protein Tyrosine Phosphatases / metabolism*
  • Response Elements / genetics
  • Suprachiasmatic Nucleus / cytology
  • Suprachiasmatic Nucleus / drug effects
  • Suprachiasmatic Nucleus / physiology*
  • Suprachiasmatic Nucleus / radiation effects
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / radiation effects
  • Vasoactive Intestinal Peptide / pharmacology*

Substances

  • Vasoactive Intestinal Peptide
  • Cyclic AMP
  • Dusp4 protein, mouse
  • Protein Tyrosine Phosphatases