Repression of a Potassium Channel by Nuclear Hormone Receptor and TGF-β Signaling Modulates Insulin Signaling in
Transforming growth factor β (TGF-β) signaling acts through Smad proteins to play fundamental roles in cell proliferation, differentiation, apoptosis, and metabolism. The Receptor associated Smads (R-Smads) interact with DNA and other nuclear proteins to regulate target gene transcription. Here, we demonstrate that the Caenorhabditis elegans R-Smad DAF-8 partners with the nuclear hormone receptor NHR-69, a C. elegans ortholog of mammalian hepatocyte nuclear factor 4α HNF4α), to repress the exp-2 potassium channel gene and increase insulin secretion. We find that NHR-69 associates with DAF-8 both in vivo and in vitro. Functionally, daf-8 nhr-69 double mutants show defects in neuropeptide secretion and phenotypes consistent with reduced insulin signaling such as increased expression of the sod-3 and gst-10 genes and a longer life span. Expression of the exp-2 gene, encoding a voltage-gated potassium channel, is synergistically increased in daf-8 nhr-69 mutants compared to single mutants and wild-type worms. In turn, exp-2 acts selectively in the ASI neurons to repress the secretion of the insulin-like peptide DAF-28. Importantly, exp-2 mutation shortens the long life span of daf-8 nhr-69 double mutants, demonstrating that exp-2 is required downstream of DAF-8 and NHR-69. Finally, animals over-expressing NHR-69 specifically in DAF-28–secreting ASI neurons exhibit a lethargic, hypoglycemic phenotype that is rescued by exogenous glucose. We propose a model whereby DAF-8/R-Smad and NHR-69 negatively regulate the transcription of exp-2 to promote neuronal DAF-28 secretion, thus demonstrating a physiological crosstalk between TGF-β and HNF4α-like signaling in C. elegans. NHR-69 and DAF-8 dependent regulation of exp-2 and DAF-28 also provides a novel molecular mechanism that contributes to the previously recognized link between insulin and TGF-β signaling in C. elegans.
Vyšlo v časopise:
Repression of a Potassium Channel by Nuclear Hormone Receptor and TGF-β Signaling Modulates Insulin Signaling in. PLoS Genet 8(2): e32767. doi:10.1371/journal.pgen.1002519
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002519
Souhrn
Transforming growth factor β (TGF-β) signaling acts through Smad proteins to play fundamental roles in cell proliferation, differentiation, apoptosis, and metabolism. The Receptor associated Smads (R-Smads) interact with DNA and other nuclear proteins to regulate target gene transcription. Here, we demonstrate that the Caenorhabditis elegans R-Smad DAF-8 partners with the nuclear hormone receptor NHR-69, a C. elegans ortholog of mammalian hepatocyte nuclear factor 4α HNF4α), to repress the exp-2 potassium channel gene and increase insulin secretion. We find that NHR-69 associates with DAF-8 both in vivo and in vitro. Functionally, daf-8 nhr-69 double mutants show defects in neuropeptide secretion and phenotypes consistent with reduced insulin signaling such as increased expression of the sod-3 and gst-10 genes and a longer life span. Expression of the exp-2 gene, encoding a voltage-gated potassium channel, is synergistically increased in daf-8 nhr-69 mutants compared to single mutants and wild-type worms. In turn, exp-2 acts selectively in the ASI neurons to repress the secretion of the insulin-like peptide DAF-28. Importantly, exp-2 mutation shortens the long life span of daf-8 nhr-69 double mutants, demonstrating that exp-2 is required downstream of DAF-8 and NHR-69. Finally, animals over-expressing NHR-69 specifically in DAF-28–secreting ASI neurons exhibit a lethargic, hypoglycemic phenotype that is rescued by exogenous glucose. We propose a model whereby DAF-8/R-Smad and NHR-69 negatively regulate the transcription of exp-2 to promote neuronal DAF-28 secretion, thus demonstrating a physiological crosstalk between TGF-β and HNF4α-like signaling in C. elegans. NHR-69 and DAF-8 dependent regulation of exp-2 and DAF-28 also provides a novel molecular mechanism that contributes to the previously recognized link between insulin and TGF-β signaling in C. elegans.
Zdroje
1. MassaguéJGomisR 2006 The logic of TGFbeta signaling. FEBS Lett 580 2811 20
2. AttisanoLCarcamoJVenturaFWeisF 1993 Identification of Human Activin and TGF Type I Receptors That Form Heteromeric Kinase Complexes. CELL-CAMBRIDGE MA- 75 671 680
3. SavageCDasPFinelliATownsendSSunC 1996 Caenorhabditis elegans genes sma-2, sma-3, and sma-4 define a conserved family of transforming growth factor beta pathway components. Proc Natl Acad Sci USA 93 790 4
4. RiddleDLSwansonMMAlbertPS 1981 Interacting genes in nematode dauer larva formation. Nature 290 668 671
5. HuP 2007 Dauer. WormBook: the online review of C elegans biology 1 19
6. SchackwitzWSInoueTThomasJH 1996 Chemosensory neurons function in parallel to mediate a pheromone response in C. elegans. Neuron 17 719 728
7. ParkDEstevezARiddleDL 2010 Antagonistic Smad transcription factors control the dauer/non-dauer switch in C. elegans. Development 137 477 485
8. YouY-jaiKimJRaizenDMAveryL 2008 Insulin, cGMP, and TGF-beta signals regulate food intake and quiescence in C. elegans: a model for satiety. Cell Metab 7 249 257
9. ShawWMLuoSLandisJAshrafJMurphyCT 2007 The C. elegans TGF-beta Dauer pathway regulates longevity via insulin signaling. Curr Biol 17 1635 1645
10. LiuTZimmermanKKPattersonGI 2004 Regulation of signaling genes by TGFbeta during entry into dauer diapause in C. elegans. BMC Dev Biol 4 11
11. HahmJ-HKimSPaikY-K 2009 Endogenous cGMP regulates adult longevity via the insulin signaling pathway in Caenorhabditis elegans. Aging Cell 8 473 483
12. LeeRYHenchJRuvkunG 2001 Regulation of C. elegans DAF-16 and its human ortholog FKHRL1 by the daf-2 insulin-like signaling pathway. Curr Biol 11 1950 1957
13. NarasimhanSDYenKBansalAKwonES 2011 PDP-1 Links the TGF-β and IIS Pathways to Regulate Longevity, Development, and Metabolism. PLoS Genet 7 e1001377 doi:10.1371/journal.pgen.1001377
14. VowelsJJThomasJH 1992 Genetic analysis of chemosensory control of dauer formation in Caenorhabditis elegans. Genetics 130 105 123
15. AntebiAYehWTaitDHedgecockERiddleD 2000 daf-12 encodes a nuclear receptor that regulates the dauer diapause and developmental age in C. elegans. Genes & Development 14 1512 27
16. AntebiA 2006 Nuclear hormone receptors in C. elegans. WormBook: the online review of C elegans biology 1 13
17. TaubertSWardJDYamamotoKR 2011 Nuclear hormone receptors in nematodes: Evolution and function. Mol Cell Endocrinol 334 49 55
18. ArdaHETaubertSMacNeilLTConineCCTsudaB 2010 Functional modularity of nuclear hormone receptors in a Caenorhabditis elegans metabolic gene regulatory network. Mol Syst Biol 6 367
19. Van GilstMRHadjivassiliouHJollyAYamamotoKR 2005 Nuclear hormone receptor NHR-49 controls fat consumption and fatty acid composition in C. elegans. PLoS Biol 3 e53 doi:10.1371/journal.pbio.0050053
20. LiangBFergusonKKadykLWattsJL 2010 The role of nuclear receptor NHR-64 in fat storage regulation in Caenorhabditis elegans. PLoS ONE 5 e9869 doi:10.1371/journal.pone.0009869
21. BrockTJBrowseJWattsJL 2006 Genetic regulation of unsaturated fatty acid composition in C. elegans. PLoS Genet 2 e108 doi:10.1371/journal.pgen.0020108
22. GissendannerCCrossgroveKKrausKMainaCSluderA 2004 Expression and function of conserved nuclear receptor genes in Caenorhabditis elegans. Dev Biol 266 399 416
23. AltschulSFGishWMillerWMyersEWLipmanDJ 1990 Basic local alignment search tool. J Mol Biol 215 403 410
24. KennedySWangDRuvkunG 2004 A conserved siRNA-degrading RNase negatively regulates RNA interference in C. elegans. Nature 427 645 649
25. JensenVLAlbertPSRiddleDL 2007 Caenorhabditis elegans SDF-9 enhances insulin/insulin-like signaling through interaction with DAF-2. Genetics 177 661 666
26. GoldenJRiddleD 1984 The Caenorhabditis elegans dauer larva: developmental effects of pheromone, food, and temperature. Developmental Biology 102 368 78
27. TissenbaumHHawdonJPerregauxMHotezPGuarenteL 2000 A common muscarinic pathway for diapause recovery in the distantly related nematode species Caenorhabditis elegans and Ancylostoma caninum. Proc Natl Acad Sci U S A 97 460 5
28. KimuraKDTissenbaumHALiuYRuvkunG 1997 daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277 942 946
29. OggSParadisSGottliebSPattersonGILeeL 1997 The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 389 994 999
30. HondaYHondaS 1999 The daf-2 gene network for longevity regulates oxidative stress resistance and Mn-superoxide dismutase gene expression in Caenorhabditis elegans. FASEB J 13 1385 1393
31. TulletJMAHertweckMAnJHBakerJHwangJY 2008 Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans. Cell 132 1025 1038
32. LiWKennedySGRuvkunG 2003 daf-28 encodes a C. elegans insulin superfamily member that is regulated by environmental cues and acts in the DAF-2 signaling pathway. Genes Dev 17 844 858
33. SpeeseSPetrieMSchuskeKAilionMAnnK 2007 UNC-31 (CAPS) is required for dense-core vesicle but not synaptic vesicle exocytosis in Caenorhabditis elegans. J Neurosci 27 6150 6162
34. FaresHGreenwaldI 2001 Regulation of endocytosis by CUP-5, the Caenorhabditis elegans mucolipin-1 homolog. Nat Genet 28 64 68
35. DeplanckeBMukhopadhyayAAoWElewaAMGroveCA 2006 A gene-centered C. elegans protein-DNA interaction network. Cell 125 1193 1205
36. DavisMWFleischhauerRDentJAJohoRHAveryL 1999 A mutation in the C. elegans EXP-2 potassium channel that alters feeding behavior. Science 286 2501 2504
37. OdomDZizlspergerNGordonDBellGRinaldiN 2004 Control of pancreas and liver gene expression by HNF transcription factors. Science 303 1378 81
38. FunabaMMathewsLS 2000 Identification and characterization of constitutively active Smad2 mutants: evaluation of formation of Smad complex and subcellular distribution. Mol Endocrinol 14 1583 1591
39. ThomasJH 1990 Genetic analysis of defecation in Caenorhabditis elegans. Genetics 124 855 872
40. KaoGNordensonCStillMRonnlundATuckS 2007 ASNA-1 positively regulates insulin secretion in C. elegans and mammalian cells. Cell 128 577 87
41. JansenGThijssenKLWernerPvan der HorstMHazendonkE 1999 The complete family of genes encoding G proteins of Caenorhabditis elegans. Nat Genet 21 414 419
42. OkkemaPGHarrisonSWPlungerVAryanaAFireA 1993 Sequence requirements for myosin gene expression and regulation in Caenorhabditis elegans. Genetics 135 385 404
43. HendersonSTJohnsonTE 2001 daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans. Current Biology 11 1975 1980
44. LteifANSchwenkWF 1999 HYPOGLYCEMIA IN INFANTS AND CHILDREN. Endocrinology & Metabolism Clinics of North America 28 619 646
45. LinH-MLeeJ-HYadavHKamarajuAKLiuE 2009 Transforming growth factor-beta/Smad3 signaling regulates insulin gene transcription and pancreatic islet beta-cell function. J Biol Chem 284 12246 12257
46. SjoholmAHellerstromC 1991 TGF-beta stimulates insulin secretion and blocks mitogenic response of pancreatic beta-cells to glucose. Am J Physiol 260 C1046 51
47. ShibataHYasudaHSekineNMineTTotsukaY 1993 Activin A increases intracellular free calcium concentrations in rat pancreatic islets. FEBS Lett 329 194 8
48. IshiyamaNShibataHKanzakiMShiozakiSMiyazakiJ 1996 Calcium as a second messenger of the action of transforming growth factor-beta on insulin secretion. Mol Cell Endocrinol 117 1 6
49. GoulleyJDahlUBaezaNMishinaYEdlundH 2007 BMP4-BMPR1A signaling in beta cells is required for and augments glucose-stimulated insulin secretion. Cell Metab 5 207 219
50. JonkLJItohSHeldinCHten DijkePKruijerW 1998 Identification and functional characterization of a Smad binding element (SBE) in the JunB promoter that acts as a transforming growth factor-beta, activin, and bone morphogenetic protein-inducible enhancer. J Biol Chem 273 21145 21152
51. JacobsonDAPhilipsonLH 2007 Action potentials and insulin secretion: new insights into the role of Kv channels. Diabetes Obes Metab 9 Suppl 2 89 98
52. HerringtonJZhouY-PBugianesiRMDulskiPMFengY 2006 Blockers of the delayed-rectifier potassium current in pancreatic beta-cells enhance glucose-dependent insulin secretion. Diabetes 55 1034 1042
53. JacobsonDAKuznetsovALopezJPKashSÄmmäläCE 2007 Kv2.1 Ablation Alters Glucose-Induced Islet Electrical Activity, Enhancing Insulin Secretion. Cell Metabolism 6 229 235
54. BargmannCHorvitzH 1991 Control of larval development by chemosensory neurons in Caenorhabditis elegans. Science 251 1243 6
55. RenPLimCSJohnsenRAlbertPSPilgrimD 1996 Control of C. elegans larval development by neuronal expression of a TGF-beta homolog. Science 274 1389 1391
56. HermanWFajansSSmithMPolonskyKBellG 1997 Diminished insulin and glucagon secretory responses to arginine in nondiabetic subjects with a mutation in the hepatocyte nuclear factor-4alpha/MODY1 gene. Diabetes 46 1749 1754
57. GuptaRVatamaniukMLeeCFlaschenRFulmerJ 2005 The MODY1 gene HNF-4alpha regulates selected genes involved in insulin secretion. J Clin Invest 115 1006 15
58. MiuraAYamagataKKakeiMHatakeyamaHTakahashiN 2006 Hepatocyte nuclear factor-4alpha is essential for glucose-stimulated insulin secretion by pancreatic beta-cells. J Biol Chem 281 5246 57
59. KardassisDPardaliKZannisVI 2000 SMAD proteins transactivate the human ApoCIII promoter by interacting physically and functionally with hepatocyte nuclear factor 4. J Biol Chem 275 41405 41414
60. LiSArmstrongCMBertinNGeHMilsteinS 2004 A map of the interactome network of the metazoan C. elegans. Science 303 540 543
61. Hahn-WindgassenAVan GilstMR 2009 The Caenorhabditis elegans HNF4alpha Homolog, NHR-31, mediates excretory tube growth and function through coordinate regulation of the vacuolar ATPase. PLoS Genet 5 e1000553 doi:10.1371/journal.pgen.1000553
62. BrennerS 1974 The genetics of Caenorhabditis elegans. Genetics 77 1 71 94
63. HobertO 2002 PCR fusion-based approach to create reporter gene constructs for expression analysis in transgenic C. elegans. BioTechniques 32 728 730
64. GandhiSSantelliJMitchellDHStilesJWSanadiDR 1980 A simple method for maintaining large, aging populations of Caenorhabditis elegans. Mech. Ageing Dev 12 137 150
65. LarsenPLAlbertPSRiddleDL 1995 Genes that regulate both development and longevity in Caenorhabditis elegans. Genetics 139 1567 1583
66. FisherRA 1970 Statistical Methods for Research Workers. 14th ed Macmillan Pub Co
67. FraserAGKamathRSZipperlenPMartinez-CamposMSohrmannM 2000 Functional genomic analysis of C. elegans chromosome I by systematic RNA interference. Nature 408 325 330
68. TimmonsLCourtDFireA 2001 Ingestion of bacterially expressed dsRNAs can produce specific and potent genetic interference in Caenorhabditis elegans. Gene 263 103 12
69. ErcanSWhittleCLiebJ 2007 Chromatin immunoprecipitation from C. elegans embryos. Nat Protoc http://www.natureprotocols.com/2007/02/15/chromatin_immunoprecipitation.php
70. BlacqueOReardonMLiCMcCarthyJ 2004 Loss of C. elegans BBS-7 and BBS-8 protein function results in cilia defects and compromised. Genes & Dev 18 13 1630 42
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2012 Číslo 2
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- Gene Expression and Stress Response Mediated by the Epigenetic Regulation of a Transposable Element Small RNA
- Contrasting Properties of Gene-Specific Regulatory, Coding, and Copy Number Mutations in : Frequency, Effects, and Dominance
- Homeobox Genes Critically Regulate Embryo Implantation by Controlling Paracrine Signaling between Uterine Stroma and Epithelium
- Nondisjunction of a Single Chromosome Leads to Breakage and Activation of DNA Damage Checkpoint in G2