Regulatory mechanism of cold-inducible diapause in Caenorhabditis elegans

<jats:title>Abstract</jats:title><jats:p>Temperature is a critical environmental cue that controls the development and lifespan of many animal species; however, mechanisms underlying low-temperature adaptation are poorly understood. Here, we describe cold-inducible diapause (CID), another type of diapause induced by low temperatures in <jats:italic>Caenorhabditis elegans</jats:italic>. A premature stop codon in heat shock factor 1 (<jats:italic>hsf-1</jats:italic>) triggers entry into CID at 9 °C, whereas wild-type animals enter CID at 4 °C. Furthermore, both wild-type and <jats:italic>hsf-1(sy441)</jats:italic> mutant animals undergoing CID can survive for weeks, and resume growth at 20 °C. Using epistasis analysis, we demonstrate that neural signalling pathways, namely tyraminergic and neuromedin U signalling, regulate entry into CID of the <jats:italic>hsf-1</jats:italic> mutant. Overexpression of anti-ageing genes, such as <jats:italic>hsf-1</jats:italic>, XBP1/<jats:italic>xbp-1</jats:italic>, FOXO<jats:italic>/daf-16</jats:italic>, Nrf2/<jats:italic>skn-1</jats:italic>, and TFEB/<jats:italic>hlh-30</jats:italic>, also inhibits CID entry of the <jats:italic>hsf-1</jats:italic> mutant. Based on these findings, we hypothesise that regulators of the <jats:italic>hsf-1</jats:italic> mutant CID may impact longevity, and successfully isolate 16 long-lived mutants among 49 non-CID mutants via genetic screening. Furthermore, we demonstrate that the nonsense mutation of MED23/<jats:italic>sur-2</jats:italic> prevents CID entry of the <jats:italic>hsf-1(sy441)</jats:italic> mutant and extends lifespan. Thus, CID is a powerful model to investigate neural networks involving cold acclimation and to explore new ageing mechanisms.</jats:p>