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 TGFb, 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/TGFb in the control of cell cycle quiescence and tissue growth: a key feature that is often misregulated in a number of hormone-dependent cancers. KEYWORDS quiescence; dauer; nuclear hormone receptor; insulin-like signaling; DAF-12; DIN-1S; par-4/LKB1; aak-2/AMPK L IKE many metazoans, Caenorhabditis elegans develops through a lengthy juvenile phase before reaching reproductive maturity; a process that includes the passage through four larval stages (L1-L4) to finally give rise to an adult hermaphrodite. However, if environmental conditions are inadequate for reproductive development, C. elegans possesses an effective means of modifying its life cycle allowing it to opt for an alternative mode of development referred to as the dauer stage. Dauer is a diapause-like stage that is specialized for dispersal and survival, where instead of progressing from the L2 to the L3 stage, L1 larvae will execute an alternative L2 stage (L2d) during which they alter their metabolic program to accumulate lipid reserves and subsequently enter the dauer stage (Kimura et al. 1997;Burnell et al. 2005). Dauer larvae are morphologically, metabolically, and behaviorally distinct from L3 stage larvae, while they exhibit a global state of cell cycle and developmental quiescence, presumably to conserve energy resources.The decision to form the dauer larva is controlled by three parallel signaling pathways whereby the reduction in TGFb, cyclic guanosine monophosphate or insulin/IGF-like signaling (...