daf-12 encodes a nuclear receptor that regulates the dauer diapause and developmental age in C. elegans.

The daf-12 gene acts at the convergence of pathways regulating larval diapause, developmental age, and adult longevity in Caenorhabditis elegans. It encodes a nuclear receptor most closely related to two C. elegans receptors, NHR-8 and NHR-48, Drosophila DHR96, and vertebrate vitamin D and pregnane-X receptors. daf-12 has three predicted protein isoforms, two of which contain DNA- and ligand-binding domains, and one of which contains the ligand-binding domain only. Mutations cluster in DNA- and ligand-binding domains, but correspond to distinct phenotypic classes. DAF-12 is expressed widely in target tissues from embryo to adult, but is upregulated during midlarval stages. In the adult, expression persists in nervous system and somatic gonad, two tissues that regulate adult longevity. We propose that DAF-12 integrates hormonal signals in cellular targets to coordinate major life history traits.

[1]  C. Kenyon,et al.  A C. elegans mutant that lives twice as long as wild type , 1993, Nature.

[2]  Thorsten Heinzel,et al.  Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor , 1995, Nature.

[3]  G. Ruvkun,et al.  The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans , 1997, Nature.

[4]  K. Miyazono,et al.  Convergence of transforming growth factor-beta and vitamin D signaling pathways on SMAD transcriptional coactivators. , 1999, Science.

[5]  Mary E. McGrath,et al.  A structural role for hormone in the thyroid hormone receptor , 1995, Nature.

[6]  R. Terns,et al.  A deficiency screen for zygotic loci required for establishment and patterning of the epidermis in Caenorhabditis elegans. , 1997, Genetics.

[7]  M. Downes,et al.  Identification and characterization of a novel corepressor interaction region in RVR and Rev-erbA alpha. , 1998, Molecular endocrinology.

[8]  G. Ruvkun,et al.  The C. elegans PTEN homolog, DAF-18, acts in the insulin receptor-like metabolic signaling pathway. , 1998, Molecular cell.

[9]  C. Kenyon,et al.  daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. , 1997, Science.

[10]  H. Horvitz,et al.  The Caenorhabditis elegans locus lin-15, a negative regulator of a tyrosine kinase signaling pathway, encodes two different proteins. , 1994, Genetics.

[11]  J. Thomas,et al.  Evidence for parallel processing of sensory information controlling dauer formation in Caenorhabditis elegans. , 1993, Genetics.

[12]  E. Frieden The Dual Role of Thyroid Hormones in Vertebrate Development and Calorigenesis , 1981 .

[13]  Jean-Paul Renaud,et al.  Crystal structure of the RAR-γ ligand-binding domain bound to all-trans retinoic acid , 1995, Nature.

[14]  Gary Ruvkun,et al.  The Caenorhabditis elegans heterochronic gene lin-14 encodes a nuclear protein that forms a temporal developmental switch , 1989, Nature.

[15]  William Bourguet,et al.  A canonical structure for the ligand-binding domain of nuclear receptors , 1996, Nature Structural Biology.

[16]  Cori Bargmann,et al.  Control of larval development by chemosensory neurons in Caenorhabditis elegans. , 1991, Science.

[17]  J. Shine,et al.  Cloning and expression of full-length cDNA encoding human vitamin D receptor. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[18]  M. Frohman,et al.  Rapid production of full-length cDNAs from rare transcripts: amplification using a single gene-specific oligonucleotide primer. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[19]  M. Chalfie,et al.  Green fluorescent protein as a marker for gene expression. , 1994, Science.

[20]  J. Apfeld,et al.  Regulation of lifespan by sensory perception in Caenorhabditis elegans , 1999, Nature.

[21]  Cynthia Kenyon,et al.  Signals from the reproductive system regulate the lifespan of C. elegans , 1999, Nature.

[22]  C. Kenyon,et al.  The age-1 and daf-2 genes function in a common pathway to control the lifespan of Caenorhabditis elegans. , 1995, Genetics.

[23]  G. Ruvkun,et al.  daf-2, daf-16 and daf-23: genetically interacting genes controlling Dauer formation in Caenorhabditis elegans. , 1994, Genetics.

[24]  Wendy S. Schackwitz,et al.  Chemosensory Neurons Function in Parallel to Mediate a Pheromone Response in C. elegans , 1996, Neuron.

[25]  W. Talbot,et al.  The drosophila EcR gene encodes an ecdysone receptor, a new member of the steroid receptor superfamily , 1991, Cell.

[26]  P. Chambon,et al.  A third human retinoic acid receptor, hRAR-gamma. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[27]  K. Umesono,et al.  The nuclear receptor superfamily: The second decade , 1995, Cell.

[28]  Donald L Riddle,et al.  Genetic and Environmental Regulation of Dauer Larva Development , 1997 .

[29]  L. Freedman Increasing the Complexity of Coactivation in Nuclear Receptor Signaling , 1999, Cell.

[30]  D. Riddle,et al.  Genes that regulate both development and longevity in Caenorhabditis elegans. , 1995, Genetics.

[31]  D. Riddle,et al.  Control of C. elegans Larval Development by Neuronal Expression of a TGF-β Homolog , 1996, Science.

[32]  V. Ambros A hierarchy of regulatory genes controls a larva-to-adult developmental switch in C. elegans , 1989, Cell.

[33]  J. Apfeld,et al.  Cell Nonautonomy of C. elegans daf-2 Function in the Regulation of Diapause and Life Span , 1998, Cell.

[34]  S. Izumo,et al.  Thyroid hormone receptor α isoforms generated by alternative splicing differentially activate myosin HC gene transcription , 1988, Nature.

[35]  C. Thummel,et al.  Isolation, regulation, and DNA-binding properties of three Drosophila nuclear hormone receptor superfamily members. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[36]  H. Horvitz,et al.  Heterochronic mutants of the nematode Caenorhabditis elegans. , 1984, Science.

[37]  Koutarou D. Kimura,et al.  daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. , 1997, Science.

[38]  J. Sulston,et al.  Post-embryonic cell lineages of the nematode, Caenorhabditis elegans. , 1977, Developmental biology.

[39]  K. Yamamoto,et al.  Crystallographic analysis of the interaction of the glucocorticoid receptor with DNA , 2003, Nature.

[40]  D L Riddle,et al.  The Caenorhabditis elegans dauer larva: developmental effects of pheromone, food, and temperature. , 1984, Developmental biology.

[41]  A. Rougvie,et al.  Similarity of the C. elegans developmental timing protein LIN-42 to circadian rhythm proteins. , 1999, Science.

[42]  R Ohlsson,et al.  Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[43]  J. Lehmann,et al.  An Orphan Nuclear Receptor Activated by Pregnanes Defines a Novel Steroid Signaling Pathway , 1998, Cell.

[44]  Andrew Smith Genome sequence of the nematode C-elegans: A platform for investigating biology , 1998 .

[45]  D. Riddle,et al.  daf-1, a C. elegans gene controlling dauer larva development, encodes a novel receptor protein kinase , 1990, Cell.

[46]  J. Lees,et al.  Identification of a conserved region required for hormone dependent transcriptional activation by steroid hormone receptors. , 1992, The EMBO journal.

[47]  Cori Bargmann,et al.  A cyclic nucleotide-gated channel inhibits sensory axon outgrowth in larval and adult Caenorhabditis elegans: a distinct pathway for maintenance of sensory axon structure. , 1998, Development.

[48]  J. White,et al.  Polyploid tissues in the nematode Caenorhabditis elegans. , 1985, Developmental biology.

[49]  B. Reinhart,et al.  The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans , 2000, Nature.

[50]  John W. R. Schwabe,et al.  The crystal structure of the estrogen receptor DNA-binding domain bound to DNA: How receptors discriminate between their response elements , 1993, Cell.

[51]  D. Riddle,et al.  Interacting genes in nematode dauer larva formation , 1981, Nature.

[52]  Caleb E. Finch,et al.  Longevity, senescence, and the genome , 1990 .

[53]  V. Ambros,et al.  Efficient gene transfer in C.elegans: extrachromosomal maintenance and integration of transforming sequences. , 1991, The EMBO journal.

[54]  D. Riddle,et al.  Two pleiotropic classes of daf-2 mutation affect larval arrest, adult behavior, reproduction and longevity in Caenorhabditis elegans. , 1998, Genetics.

[55]  W. Talbot,et al.  Drosophila Ecdysone Receptor Mutations Reveal Functional Differences among Receptor Isoforms , 1997, Cell.

[56]  G. Ruvkun,et al.  The DAF-3 Smad protein antagonizes TGF-beta-related receptor signaling in the Caenorhabditis elegans dauer pathway. , 1997, Genes & development.

[57]  G. Ruvkun,et al.  A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans , 1996, Nature.

[58]  Cell and Growth Cone Migrations , 1997 .

[59]  V. Chatterjee,et al.  Thyroid hormone resistance syndrome manifests as an aberrant interaction between mutant T3 receptors and transcriptional corepressors. , 1997, Molecular endocrinology.

[60]  V. Ambros,et al.  The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14 , 1993, Cell.

[61]  J. Berg Genome sequence of the nematode C. elegans: a platform for investigating biology. , 1998, Science.

[62]  Wendy S. Schackwitz,et al.  Mutations affecting the chemosensory neurons of Caenorhabditis elegans. , 1995, Genetics.

[63]  R. Evans,et al.  Nuclear receptor that identifies a novel retinoic acid response pathway , 1990, Nature.

[64]  R. D. Campbell,et al.  Reactivity of cytosine and thymine in single-base-pair mismatches with hydroxylamine and osmium tetroxide and its application to the study of mutations. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[65]  D. Riddle,et al.  The daf-4 gene encodes a bone morphogenetic protein receptor controlling C. elegans dauer larva development , 1993, Nature.

[66]  J. Culotti,et al.  daf-12 regulates developmental age and the dauer alternative in Caenorhabditis elegans. , 1998, Development.

[67]  N. Halloran,et al.  A survey of expressed genes in Caenorhabditis elegans , 1992, Nature Genetics.

[68]  T. Johnson,et al.  A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility. , 2002, Genetics.

[69]  J. Thomas,et al.  Multiple chemosensory defects in daf-11 and daf-21 mutants of Caenorhabditis elegans. , 1994, Genetics.

[70]  William Bourguet,et al.  Crystal structure of the ligand-binding domain of the human nuclear receptor RXR-α , 1995, Nature.

[71]  J. Thomas,et al.  Genetic analysis of chemosensory control of dauer formation in Caenorhabditis elegans. , 1992, Genetics.

[72]  A. Sluder,et al.  The nuclear receptor superfamily has undergone extensive proliferation and diversification in nematodes. , 1999, Genome research.

[73]  M. Lazar,et al.  The CoRNR motif controls the recruitment of corepressors by nuclear hormone receptors , 1999, Nature.

[74]  V. Ambros,et al.  The Cold Shock Domain Protein LIN-28 Controls Developmental Timing in C. elegans and Is Regulated by the lin-4 RNA , 1997, Cell.

[75]  G. Ruvkun,et al.  Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans , 1993, Cell.

[76]  V. Ambros,et al.  Heterochronic genes control the stage-specific initiation and expression of the dauer larva developmental program in Caenorhabditis elegans. , 1989, Genes & Development.

[77]  J. Barry,et al.  Temporal reiteration of a precise gene expression pattern during nematode development. , 1996, The EMBO journal.

[78]  James H. Thomas,et al.  Targets of TGF-β Signaling in Caenorhabditis elegans Dauer Formation , 2000 .

[79]  A. Rougvie,et al.  The heterochronic gene lin-29 encodes a zinc finger protein that controls a terminal differentiation event in Caenorhabditis elegans. , 1995, Development.