Developmental and Cell Cycle Quiescence Is Mediated by the Nuclear Hormone Receptor Coregulator DIN-1S in the Caenorhabditis elegans Dauer Larva.
When faced with suboptimal growth conditions, Caenorhabditis elegans larvae can enter a diapause-like stage called "dauer" that is specialized for dispersal and survival. The decision to form a dauer larva is controlled by three parallel signaling pathways, whereby a compromise of TGFβ, cyclic guanosine monophosphate, or insulin/IGF-like signaling (ILS) results in dauer formation. Signals from these pathways converge on DAF-12, a nuclear hormone receptor that triggers the changes required to initiate dauer formation. DAF-12 is related to the vitamin D, liver-X, and androstane receptors, and like these human receptors, it responds to lipophilic hormone ligands. When bound to its ligand, DAF-12 acquires transcriptional activity that directs reproductive development, while unliganded DAF-12 forms a dauer-specifying complex with its interacting protein DIN-1S to regulate the transcription of genes required for dauer development. We report here that din-1S is required in parallel to par-4/LKB1 signaling within the gonad to establish cell cycle quiescence during the onset of the dauer stage. We show that din-1S is important for postdauer reproduction when ILS is impaired and is necessary for long-term dauer survival in response to reduced ILS. Our work uncovers several previously uncharacterized functions of DIN-1S in executing and maintaining many of the cellular and physiological processes required for appropriate dauer arrest, while also shedding light on the coordination of nuclear hormone signaling, the LKB1/AMPK signaling cascade, and ILS/TGFβ in the control of cell cycle quiescence and tissue growth: a key feature that is often misregulated in a number of hormone-dependent cancers.
Department of Biology, McGill University, Montréal, Québec, Canada H3A 1B1.
Eileen
E
Colella
Department of Biology, McGill University, Montréal, Québec, Canada H3A 1B1.
Shaolin
S
Li
Department of Biology, McGill University, Montréal, Québec, Canada H3A 1B1 richard.roy@mcgill.ca.
Richard
R
Roy
D000731:Androstanes / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development; D029742:Caenorhabditis elegans Proteins / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics; D006066:Gonads / Q000254:growth & development / Q000378:metabolism; D006728:Hormones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000235:genetics; D007814:Larva / Q000235:genetics / Q000254:growth & development; D008675:Metamorphosis, Biological / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000235:genetics*
D000731:Androstanes; D029742:Caenorhabditis elegans Proteins; C410905:DAF-12 protein, C elegans; C492744:Din-1 protein, C elegans; D006728:Hormones; D007328:Insulin; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C097238:PAR-3 protein, C elegans; D017346:Protein Serine-Threonine Kinases; C033936:androstane
DAF-12; DIN-1S; aak-2/AMPK; dauer; insulin-like signaling; nuclear hormone receptor; par-4/LKB1; quiescence