Identification of Ligands for DAF-12 that Govern Dauer Formation and Reproduction in C. elegans

Howard Hughes Medical Institute and Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Cell (Impact Factor: 32.24). 04/2006; 124(6):1209-23. DOI: 10.1016/j.cell.2006.01.037
Source: PubMed


In response to environmental and dietary cues, the C. elegans orphan nuclear receptor, DAF-12, regulates dauer diapause, reproductive development, fat metabolism, and life span. Despite strong evidence for hormonal control, the identification of the DAF-12 ligand has remained elusive. In this work, we identified two distinct 3-keto-cholestenoic acid metabolites of DAF-9, a cytochrome P450 involved in hormone production, that function as ligands for DAF-12. At nanomolar concentrations, these steroidal ligands (called dafachronic acids) bind and transactivate DAF-12 and rescue the hormone deficiency of daf-9 mutants. Interestingly, DAF-9 has a biochemical activity similar to mammalian CYP27A1 catalyzing addition of a terminal acid to the side chain of sterol metabolites. Together, these results define the first steroid hormones in nematodes as ligands for an invertebrate orphan nuclear receptor and demonstrate that steroidal regulation of reproduction, from biology to molecular mechanism, is conserved from worms to humans.

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    • "It is intriguing that DA deficiency did not drive these Daf-d mutants into the dauer state. In the case of the daf-12 mutant, it is understandable because the dauer program is turned on by ligand-free DAF-12 together with its corepressor DIN-1 (Ludewig et al. 2004), which competes with DA for DAF-12 binding (Motola et al. 2006). In the absence of DAF-12, DIN-1 itself cannot induce dauer formation. "
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    ABSTRACT: The steroid hormone dafachronic acid (DA) regulates dauer formation and lifespan in Caenorhabditis elegans by binding to the nuclear receptor DAF-12. However, little is known about how DA concentrations change under various physiological conditions and about how DA/DAF-12 signaling interacts with other signaling pathways that also regulate dauer formation and lifespan. Using a sensitive bioanalytical method, we quantified the endogenous DA concentrations in a long-lived germline-less glp-1 mutant and in the dauer-formation defective (Daf-d) mutants daf-12, daf-16, daf-5, and daf-3. We found that the DA concentration in the glp-1 mutant was similar to that in the WT. This result is contrary to the long-held belief that germline loss-induced longevity involves increased DA production, and suggests instead that this type of longevity involves an enhanced response to DA. We also found evidence suggesting that increased DA sensitivity underlies lifespan extension triggered by exogenous DA. At the L2/L3 stage, the DA concentration in a daf-12 null mutant decreased to 22% of the WT level. This finding is consistent with the previously proposed positive feedback regulation between DAF-12 and DA production. Surprisingly, the DA concentrations in the daf-16, daf-5, and daf-3 mutants were only 19-34% of the WT level at the L2/L3 stage, slightly higher than those in the dauer-formation constitutive (Daf-c) mutants at the pre-dauer stage (4%-15% of the WT L2 control). Our experimental evidence suggested that the positive feedback between DA and DAF-12 was partially induced in the three Daf-d mutants. Copyright © 2015 Author et al.
    Full-text · Article · May 2015 · G3-Genes Genomes Genetics
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    • "The somatic cell expression pattern and specific functions in reproduction may indicate some proteins bound by UBiL with the conserved feature Gly-Gly dipeptide (Monia et al., 1990; Mourtada-Maarabouni et al., 2004) to regulate gonadal cell development (Fig. 9). IIS (Kimura et al., 1997), TGF-b (Birnby et al., 2000), cGMP (Ren et al., 1996), DA (Motola et al., 2006; Crook, 2014), AP (Angelo and Van Gilst, 2009) and FA metabolism (Joo et al., 2009) are all wellstudied pathways related to dauer formation in C. elegans. Genes from these pathways (Lant and Storey, 2010) were down-regulated significantly in Ce-rps30RNAi worms, except for daf-16 and akt-1, both of which are components of the IIS pathway (Ogg et al., 1997). "

    Full-text · Dataset · Feb 2015
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    • "DAF- 12-mediated longevity is achieved through a signaling molecule secreted from the somatic gonad and other steroidogenic tissues, including the hypodermis and the neuroendocrine XXX cells in the head (Gerisch et al. 2001; Yamawaki et al. 2010). The corresponding signaling molecule is a bile acid-like steroid called dafachronic acid that directly binds DAF-12 and triggers its transcriptional activity in the target tissues (Table 1; Motola et al. 2006). "
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    ABSTRACT: Protein quality control is essential in all organisms and regulated by the proteostasis network (PN) and cell stress response pathways that maintain a functional proteome to promote cellular health. In this review, we describe how metazoans employ multiple modes of cell-nonautonomous signaling across tissues to integrate and transmit the heat-shock response (HSR) for balanced expression of molecular chaperones. The HSR and other cell stress responses such as the unfolded protein response (UPR) can function autonomously in single-cell eukaryotes and tissue culture cells; however, within the context of a multicellular animal, the PN is regulated by cell-nonautonomous signaling through specific sensory neurons and by the process of transcellular chaperone signaling. These newly identified forms of stress signaling control the PN between neurons and nonneuronal somatic tissues to achieve balanced tissue expression of chaperones in response to environmental stress and to ensure that metastable aggregation-prone proteins expressed within any single tissue do not generate local proteotoxic risk. Transcellular chaperone signaling leads to the compensatory expression of chaperones in other somatic tissues of the animal, perhaps preventing the spread of proteotoxic damage. Thus, communication between subcellular compartments and across different cells and tissues maintains proteostasis when challenged by acute stress and upon chronic expression of metastable proteins. We propose that transcellular chaperone signaling provides a critical control step for the PN to maintain cellular and organismal health span.
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