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The Atypical Calpains: Evolutionary Analyses and Roles in Cellular Degeneration


The calpains are physiologically important Ca2+-activated regulatory proteases, which are divided into typical or atypical sub-families based on constituent domains. Both sub-families are present in mammals, but our understanding of calpain function is based primarily on typical sub-family members. Here, we take advantage of the model organism Caenorhabditis elegans, which expresses only atypical calpains, to extend our knowledge of the phylogenetic evolution and function of calpains. We provide evidence that a typical human calpain protein with a penta EF hand, detected using custom profile hidden Markov models, is conserved in ancient metazoans and a divergent clade. These analyses also provide evidence for the lineage-specific loss of typical calpain genes in C. elegans and Ciona, and they reveal that many calpain-like genes lack an intact catalytic triad. Given the association between the dysregulation of typical calpains and human degenerative pathologies, we explored the phenotypes, expression profiles, and consequences of inappropriate reduction or activation of C. elegans atypical calpains. These studies show that the atypical calpain gene, clp-1, contributes to muscle degeneration and reveal that clp-1 activity is sensitive to genetic manipulation of [Ca2+]i. We show that CLP-1 localizes to sarcomeric sub-structures, but is excluded from dense bodies (Z-disks). We find that the muscle degeneration observed in a C. elegans model of dystrophin-based muscular dystrophy can be suppressed by clp-1 inactivation and that nemadipine-A inhibition of the EGL-19 calcium channel reveals that Ca2+ dysfunction underlies the C. elegans MyoD model of myopathy. Taken together, our analyses highlight the roles of calcium dysregulation and CLP-1 in muscle myopathies and suggest that the atypical calpains could retain conserved roles in myofilament turnover.


Vyšlo v časopise: The Atypical Calpains: Evolutionary Analyses and Roles in Cellular Degeneration. PLoS Genet 8(3): e32767. doi:10.1371/journal.pgen.1002602
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002602

Souhrn

The calpains are physiologically important Ca2+-activated regulatory proteases, which are divided into typical or atypical sub-families based on constituent domains. Both sub-families are present in mammals, but our understanding of calpain function is based primarily on typical sub-family members. Here, we take advantage of the model organism Caenorhabditis elegans, which expresses only atypical calpains, to extend our knowledge of the phylogenetic evolution and function of calpains. We provide evidence that a typical human calpain protein with a penta EF hand, detected using custom profile hidden Markov models, is conserved in ancient metazoans and a divergent clade. These analyses also provide evidence for the lineage-specific loss of typical calpain genes in C. elegans and Ciona, and they reveal that many calpain-like genes lack an intact catalytic triad. Given the association between the dysregulation of typical calpains and human degenerative pathologies, we explored the phenotypes, expression profiles, and consequences of inappropriate reduction or activation of C. elegans atypical calpains. These studies show that the atypical calpain gene, clp-1, contributes to muscle degeneration and reveal that clp-1 activity is sensitive to genetic manipulation of [Ca2+]i. We show that CLP-1 localizes to sarcomeric sub-structures, but is excluded from dense bodies (Z-disks). We find that the muscle degeneration observed in a C. elegans model of dystrophin-based muscular dystrophy can be suppressed by clp-1 inactivation and that nemadipine-A inhibition of the EGL-19 calcium channel reveals that Ca2+ dysfunction underlies the C. elegans MyoD model of myopathy. Taken together, our analyses highlight the roles of calcium dysregulation and CLP-1 in muscle myopathies and suggest that the atypical calpains could retain conserved roles in myofilament turnover.


Zdroje

1. SorimachiHHataSOnoY 2010 Expanding members and roles of the calpain superfamily and their genetically modified animals. Exp Anim 59 549 566

2. StroblSFernandez-CatalanCBraunMHuberRMasumotoH 2000 The crystal structure of calcium-free human m-calpain suggests an electrostatic switch mechanism for activation by calcium. Proc Natl Acad Sci U S A 97 588 592

3. HosfieldCMElceJSDaviesPLJiaZ 1999 Crystal structure of calpain reveals the structural basis for Ca(2+)-dependent protease activity and a novel mode of enzyme activation. EMBO J 18 6880 6889

4. LinGDChattopadhyayDMakiMWangKKCarsonM 1997 Crystal structure of calcium bound domain VI of calpain at 1.9 A resolution and its role in enzyme assembly, regulation, and inhibitor binding. Nat Struct Biol 4 539 547

5. BlanchardHGrochulskiPLiYArthurJSDaviesPL 1997 Structure of a calpain Ca(2+)-binding domain reveals a novel EF-hand and Ca(2+)-induced conformational changes. Nat Struct Biol 4 532 538

6. SorimachiHSuzukiK 2001 The structure of calpain. J Biochem 129 653 664

7. GollDEThompsonVFLiHWeiWCongJ 2003 The calpain system. Physiol Rev 83 731 801

8. MoldoveanuTHosfieldCMLimDElceJSJiaZ 2002 A Ca(2+) switch aligns the active site of calpain. Cell 108 649 660

9. HataSDoiNKitamuraFSorimachiH 2007 Stomach-specific calpain, nCL-2/calpain 8, is active without calpain regulatory subunit and oligomerizes through C2-like domains. J Biol Chem 282 27847 27856

10. KinbaraKIshiuraSTomiokaSSorimachiHJeongSY 1998 Purification of native p94, a muscle-specific calpain, and characterization of its autolysis. Biochem J 335 Pt 3 589 596

11. RavulapalliRDiazBGCampbellRLDaviesPL 2005 Homodimerization of calpain 3 penta-EF-hand domain. Biochem J 388 585 591

12. NishimuraTGollDE 1991 Binding of calpain fragments to calpastatin. J Biol Chem 266 11842 11850

13. OtsukaYGollDE 1987 Purification of the Ca2+-dependent proteinase inhibitor from bovine cardiac muscle and its interaction with the millimolar Ca2+-dependent proteinase. J Biol Chem 262 5839 5851

14. CroallDEErsfeldK 2007 The calpains: modular designs and functional diversity. Genome Biol 8 218

15. StorrSJCarragherNOFrameMCParrTMartinSG 2011 The calpain system and cancer. Nat Rev Cancer 11 364 374

16. FriedrichPTompaPFarkasA 2004 The calpain-system of Drosophila melanogaster: coming of age. Bioessays 26 1088 1096

17. Consortium 1998 Genome sequence of the nematode C. elegans: a platform for investigating biology. Science 282 2012 2018

18. LebartMCBenyaminY 2006 Calpain involvement in the remodeling of cytoskeletal anchorage complexes. FEBS J 273 3415 3426

19. FrancoSJHuttenlocherA 2005 Regulating cell migration: calpains make the cut. J Cell Sci 118 3829 3838

20. GollDENetiGMaresSWThompsonVF 2008 Myofibrillar protein turnover: the proteasome and the calpains. J Anim Sci 86 E19 35

21. EvansJSTurnerMD 2007 Emerging functions of the calpain superfamily of cysteine proteases in neuroendocrine secretory pathways. J Neurochem 103 849 859

22. JanossyJUbezioPApatiAMagocsiMTompaP 2004 Calpain as a multi-site regulator of cell cycle. Biochem Pharmacol 67 1513 1521

23. JohnsonJDHanZOtaniKYeHZhangY 2004 RyR2 and calpain-10 delineate a novel apoptosis pathway in pancreatic islets. J Biol Chem 279 24794 24802

24. TomimatsuYIdemotoSMoriguchiSWatanabeSNakanishiH 2002 Proteases involved in long-term potentiation. Life Sci 72 355 361

25. RichardIBrouxOAllamandVFougerousseFChiannilkulchaiN 1995 Mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A. Cell 81 27 40

26. HorikawaYOdaNCoxNJLiXOrho-MelanderM 2000 Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet 26 163 175

27. YoshikawaYMukaiHHinoFAsadaKKatoI 2000 Isolation of two novel genes, down-regulated in gastric cancer. Jpn J Cancer Res 91 459 463

28. HataSAbeMSuzukiHKitamuraFToyama-SorimachiN 2010 Calpain 8/nCL-2 and calpain 9/nCL-4 constitute an active protease complex, G-calpain, involved in gastric mucosal defense. PLoS Genet 6 e1001040 doi:10.1371/journal.pgen.1001040

29. TompaPBuzder-LantosPTantosAFarkasASzilagyiA 2004 On the sequential determinants of calpain cleavage. J Biol Chem 279 20775 20785

30. CuerrierDMoldoveanuTDaviesPL 2005 Determination of peptide substrate specificity for mu-calpain by a peptide library-based approach: the importance of primed side interactions. J Biol Chem 280 40632 40641

31. CarragherNO 2006 Calpain inhibition: a therapeutic strategy targeting multiple disease states. Curr Pharm Des 12 615 638

32. TurkVTurkBGuncarGTurkDKosJ 2002 Lysosomal cathepsins: structure, role in antigen processing and presentation, and cancer. Adv Enzyme Regul 42 285 303

33. BarnesTMHodgkinJ 1996 The tra-3 sex determination gene of Caenorhabditis elegans encodes a member of the calpain regulatory protease family. EMBO J 15 4477 4484

34. SokolSBKuwabaraPE 2000 Proteolysis in Caenorhabditis elegans sex determination: cleavage of TRA-2A by TRA-3. Genes Dev 14 901 906

35. SyntichakiPXuKDriscollMTavernarakisN 2002 Specific aspartyl and calpain proteases are required for neurodegeneration in C. elegans. Nature 419 939 944

36. HuangLHanna-RoseW 2006 EGF signaling overcomes a uterine cell death associated with temporal mis-coordination of organogenesis within the C. elegans egg-laying apparatus. Dev Biol 300 599 611

37. LukeCJPakSCAskewYSNavigliaTLAskewDJ 2007 An intracellular serpin regulates necrosis by inhibiting the induction and sequelae of lysosomal injury. Cell 130 1108 1119

38. SteinLDBaoZBlasiarDBlumenthalTBrentMR 2003 The genome sequence of Caenorhabditis briggsae: a platform for comparative genomics. PLoS Biol 1 e45 doi:10.1371/journal.pbio.0000045

39. SrivastavaMBegovicEChapmanJPutnamNHHellstenU 2008 The Trichoplax genome and the nature of placozoans. Nature 454 955 960

40. PutnamNHSrivastavaMHellstenUDirksBChapmanJ 2007 Sea anemone genome reveals ancestral eumetazoan gene repertoire and genomic organization. Science 317 86 94

41. ChapmanJAKirknessEFSimakovOHampsonSEMitrosT 2010 The dynamic genome of Hydra. Nature 464 592 596

42. SrivastavaMSimakovOChapmanJFaheyBGauthierME 2010 The Amphimedon queenslandica genome and the evolution of animal complexity. Nature 466 720 726

43. DehalPSatouYCampbellRKChapmanJDegnanB 2002 The draft genome of Ciona intestinalis: insights into chordate and vertebrate origins. Science 298 2157 2167

44. BatemanACoinLDurbinRFinnRDHollichV 2004 The Pfam protein families database. Nucleic Acids Res 32 D138 141

45. EddySR 1998 Profile hidden Markov models. Bioinformatics 14 755 763

46. TonamiKKuriharaYAburataniHUchijimaYAsanoT 2007 Calpain 6 is involved in microtubule stabilization and cytoskeletal organization. Mol Cell Biol 27 2548 2561

47. ConsortiumU 2011 Ongoing and future developments at the Universal Protein Resource. Nucleic Acids Res 39 D214 219

48. BradleyRKRobertsASmootMJuvekarSDoJ 2009 Fast statistical alignment. PLoS Comput Biol 5 e1000392 doi:10.1371/journal.pcbi.1000392

49. SimmerFMoormanCvan der LindenAMKuijkEvan den BerghePV 2003 Genome-wide RNAi of C. elegans using the hypersensitive rrf-3 strain reveals novel gene functions. PLoS Biol 1 e12 doi:10.1371/journal.pbio.0000012

50. HodgkinJ 1986 Sex determination in the nematode C. elegans: analysis of tra-3 suppressors and characterization of fem genes. Genetics 114 15 52

51. DuttPCroallDEArthurJSVeyraTDWilliamsK 2006 m-Calpain is required for preimplantation embryonic development in mice. BMC Dev Biol 6 3

52. RaynaudFMarcilhacAChebliKBenyaminYRosselM 2008 Calpain 2 expression pattern and sub-cellular localization during mouse embryogenesis. Int J Dev Biol 52 383 388

53. BiswasSHarrisFPhoenixDA 2001 Treatment of cataracts - vision for the future. Biologist (London) 48 273 277

54. SpencerMJMellgrenRL 2002 Overexpression of a calpastatin transgene in mdx muscle reduces dystrophic pathology. Hum Mol Genet 11 2645 2655

55. YamashimaT 2000 Implication of cysteine proteases calpain, cathepsin and caspase in ischemic neuronal death of primates. Prog Neurobiol 62 273 295

56. StringhamEGDixonDKJonesDCandidoEP 1992 Temporal and spatial expression patterns of the small heat shock (hsp16) genes in transgenic Caenorhabditis elegans. Mol Biol Cell 3 221 233

57. MillerDMStockdaleFEKarnJ 1986 Immunological identification of the genes encoding the four myosin heavy chain isoforms of Caenorhabditis elegans. Proc Natl Acad Sci U S A 83 2305 2309

58. ArthurJSGauthierSElceJS 1995 Active site residues in m-calpain: identification by site-directed mutagenesis. FEBS Lett 368 397 400

59. RaserKJPosnerAWangKK 1995 Casein zymography: a method to study mu-calpain, m-calpain, and their inhibitory agents. Arch Biochem Biophys 319 211 216

60. GieselerKGrisoniKSegalatL 2000 Genetic suppression of phenotypes arising from mutations in dystrophin-related genes in Caenorhabditis elegans. Curr Biol 10 1092 1097

61. KellyWGXuSMontgomeryMKFireA 1997 Distinct requirements for somatic and germline expression of a generally expressed Caernorhabditis elegans gene. Genetics 146 227 238

62. HagedornEJYashiroHZielJWIharaSWangZ 2009 Integrin acts upstream of netrin signaling to regulate formation of the anchor cell's invasive membrane in C. elegans. Dev Cell 17 187 198

63. KoenigMHoffmanEPBertelsonCJMonacoAPFeenerC 1987 Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals. Cell 50 509 517

64. BessouCGiugiaJBFranksCJHolden-DyeLSegalatL 1998 Mutations in the Caenorhabditis elegans dystrophin-like gene dys-1 lead to hyperactivity and suggest a link with cholinergic transmission. Neurogenetics 2 61 72

65. Carre-PierratMGrisoniKGieselerKMariolMCMartinE 2006 The SLO-1 BK channel of Caenorhabditis elegans is critical for muscle function and is involved in dystrophin-dependent muscle dystrophy. J Mol Biol 358 387 395

66. BaylisHAFuruichiTYoshikawaFMikoshibaKSattelleDB 1999 Inositol 1,4,5-trisphosphate receptors are strongly expressed in the nervous system, pharynx, intestine, gonad and excretory cell of Caenorhabditis elegans and are encoded by a single gene (itr-1). J Mol Biol 294 467 476

67. KimHRogersMJRichmondJEMcIntireSL 2004 SNF-6 is an acetylcholine transporter interacting with the dystrophin complex in Caenorhabditis elegans. Nature 430 891 896

68. GieselerKBessouCSegalatL 1999 Dystrobrevin- and dystrophin-like mutants display similar phenotypes in the nematode Caenorhabditis elegans. Neurogenetics 2 87 90

69. GrisoniKGieselerKMariolMCMartinECarre-PierratM 2003 The stn-1 syntrophin gene of C.elegans is functionally related to dystrophin and dystrobrevin. J Mol Biol 332 1037 1046

70. LapidosKAKakkarRMcNallyEM 2004 The dystrophin glycoprotein complex: signaling strength and integrity for the sarcolemma. Circ Res 94 1023 1031

71. MariolMCSegalatL 2001 Muscular degeneration in the absence of dystrophin is a calcium-dependent process. Curr Biol 11 1691 1694

72. KwokTCRickerNFraserRChanAWBurnsA 2006 A small-molecule screen in C. elegans yields a new calcium channel antagonist. Nature 441 91 95

73. AguinaldoAMTurbevilleJMLinfordLSRiveraMCGareyJR 1997 Evidence for a clade of nematodes, arthropods and other moulting animals. Nature 387 489 493

74. TakanoJTomiokaMTsubukiSHiguchiMIwataN 2005 Calpain mediates excitotoxic DNA fragmentation via mitochondrial pathways in adult brains: evidence from calpastatin mutant mice. J Biol Chem 280 16175 16184

75. RizoJSudhofTC 1998 C2-domains, structure and function of a universal Ca2+-binding domain. J Biol Chem 273 15879 15882

76. MegeneyLAKablarBGarrettKAndersonJERudnickiMA 1996 MyoD is required for myogenic stem cell function in adult skeletal muscle. Genes Dev 10 1173 1183

77. GaillyPDe BackerFVan SchoorMGillisJM 2007 In situ measurements of calpain activity in isolated muscle fibres from normal and dystrophin-lacking mdx mice. J Physiol 582 1261 1275

78. HopfFWTurnerPRSteinhardtRA 2007 Calcium misregulation and the pathogenesis of muscular dystrophy. Subcell Biochem 45 429 464

79. AllenDGZhangBTWhiteheadNP 2010 Stretch-induced membrane damage in muscle: comparison of wild-type and mdx mice. Adv Exp Med Biol 682 297 313

80. BanoDYoungKWGuerinCJLefeuvreRRothwellNJ 2005 Cleavage of the plasma membrane Na+/Ca2+ exchanger in excitotoxicity. Cell 120 275 285

81. KopilCMVaisHCheungKHSiebertAPMakDO Calpain-cleaved type 1 inositol 1,4,5-trisphosphate receptor (InsP(3)R1) has InsP(3)-independent gating and disrupts intracellular Ca(2+) homeostasis. J Biol Chem 286 35998 36010

82. Shoshan-BarmatzVWeilSMeyerHVarsanyiMHeilmeyerLM 1994 Endogenous, Ca(2+)-dependent cysteine-protease cleaves specifically the ryanodine receptor/Ca2+ release channel in skeletal muscle. J Membr Biol 142 281 288

83. DaytonWR 1982 Comparison of low- and high-calcium-requiring forms of the calcium-activated protease with their autocatalytic breakdown products. Biochim Biophys Acta 709 166 172

84. KumamotoTKleeseWCCongJYGollDEPiercePR 1992 Localization of the Ca(2+)-dependent proteinases and their inhibitor in normal, fasted, and denervated rat skeletal muscle. Anat Rec 232 60 77

85. Di LisaFDe TullioRSalaminoFBarbatoRMelloniE 1995 Specific degradation of troponin T and I by mu-calpain and its modulation by substrate phosphorylation. Biochem J 308 Pt 1 57 61

86. RaynaudFBonnalCFernandezEBremaudLCeruttiM 2003 The calpain 1-alpha-actinin interaction. Resting complex between the calcium-dependent protease and its target in cytoskeleton. Eur J Biochem 270 4662 4670

87. GalvezASDiwanAOdleyAMHahnHSOsinskaH 2007 Cardiomyocyte degeneration with calpain deficiency reveals a critical role in protein homeostasis. Circ Res 100 1071 1078

88. NetiGNovakSMThompsonVFGollDE 2009 Properties of easily releasable myofilaments: are they the first step in myofibrillar protein turnover? Am J Physiol Cell Physiol 296 C1383 1390

89. FoxRMWatsonJDVon StetinaSEMcDermottJBrodiganTM 2007 The embryonic muscle transcriptome of Caenorhabditis elegans. Genome Biol 8 R188

90. SokolSB 2000 Regulatory proteolysis in C. elegans sex determination: Molecular, genetic and biochemical analysis of the calpain protease TRA-3 Cambridge Cambridge

91. EtheridgeTOczypokEALehmannSFieldsBDShephardF Calpains Mediate Integrin Attachment Complex Maintenance of Adult Muscle in Caenorhabditis elegans. PLoS Genet 8 e1002471 doi:10.1371/journal.pgen.1002471

92. MeissnerBWarnerAWongKDubeNLorchA 2009 An integrated strategy to study muscle development and myofilament structure in Caenorhabditis elegans. PLoS Genet 5 e1000537 doi:10.1371/journal.pgen.1000537

93. GhoshSRHopeIA 2010 Determination of the mobility of novel and established Caenorhabditis elegans sarcomeric proteins in vivo. Eur J Cell Biol 89 437 448

94. GrisoniKMartinEGieselerKMariolMCSegalatL 2002 Genetic evidence for a dystrophin-glycoprotein complex (DGC) in Caenorhabditis elegans. Gene 294 77 86

95. LecroiseyCMartinEMariolMCGrangerLSchwabY 2008 DYC-1, a protein functionally linked to dystrophin in Caenorhabditis elegans is associated with the dense body, where it interacts with the muscle LIM domain protein ZYX-1. Mol Biol Cell 19 785 796

96. DargelosEPoussardSBruleCDauryLCottinP 2008 Calcium-dependent proteolytic system and muscle dysfunctions: a possible role of calpains in sarcopenia. Biochimie 90 359 368

97. FraysseBDesaphyJFRollandJFPiernoSLiantonioA 2006 Fiber type-related changes in rat skeletal muscle calcium homeostasis during aging and restoration by growth hormone. Neurobiol Dis 21 372 380

98. AnderssonDCBetzenhauserMJReikenSMeliACUmanskayaA 2011 Ryanodine receptor oxidation causes intracellular calcium leak and muscle weakness in aging. Cell Metab 14 196 207

99. MakiMNarayanaSVHitomiK 1997 A growing family of the Ca2+-binding proteins with five EF-hand motifs. Biochem J 328 Pt 2 718 720

100. BrennerS 1974 The genetics of Caenorhabditis elegans. Genetics 77 71 94

101. HarfeBDBrandaCSKrauseMSternMJFireA 1998 MyoD and the specification of muscle and non-muscle fates during postembryonic development of the C. elegans mesoderm. Development 125 2479 2488

102. LeeRYLobelLHengartnerMHorvitzHRAveryL 1997 Mutations in the alpha1 subunit of an L-type voltage-activated Ca2+ channel cause myotonia in Caenorhabditis elegans. EMBO J 16 6066 6076

103. ClandininTRDeModenaJASternbergPW 1998 Inositol trisphosphate mediates a RAS-independent response to LET-23 receptor tyrosine kinase activation in C. elegans. Cell 92 523 533

104. DaviesAGPierce-ShimomuraJTKimHVanHovenMKThieleTR 2003 A central role of the BK potassium channel in behavioral responses to ethanol in C. elegans. Cell 115 655 666

105. ZhaoGZhaoYPanBLiuJHuangX 2007 Hypersensitivity of BKCa to Ca2+ sparks underlies hyporeactivity of arterial smooth muscle in shock. Circ Res 101 493 502

106. BarnesTMJinYHorvitzHRRuvkunGHekimiS 1996 The Caenorhabditis elegans behavioral gene unc-24 encodes a novel bipartite protein similar to both erythrocyte band 7.2 (stomatin) and nonspecific lipid transfer protein. J Neurochem 67 46 57

107. PriceMPThompsonRJEshcolJOWemmieJABensonCJ 2004 Stomatin modulates gating of acid-sensing ion channels. J Biol Chem 279 53886 53891

108. SedenskyMMSiefkerJMKohJYMillerDM3rdMorganPG 2004 A stomatin and a degenerin interact in lipid rafts of the nervous system of Caenorhabditis elegans. Am J Physiol Cell Physiol 287 C468 474

109. ZhangSArnadottirJKellerCCaldwellGAYaoCA 2004 MEC-2 is recruited to the putative mechanosensory complex in C. elegans touch receptor neurons through its stomatin-like domain. Curr Biol 14 1888 1896

110. TimmonsLCourtDLFireA 2001 Ingestion of bacterially expressed dsRNAs can produce specific and potent genetic interference in Caenorhabditis elegans. Gene 263 103 112

111. KamathRSAhringerJ 2003 Genome-wide RNAi screening in Caenorhabditis elegans. Methods 30 313 321

112. LivakKJSchmittgenTD 2001 Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods 25 402 408

113. MelloCFireA 1995 DNA transformation. Methods Cell Biol 48 451 482

114. LimYSMallapurSKaoGRenXCWadsworthWG 1999 Netrin UNC-6 and the regulation of branching and extension of motoneuron axons from the ventral nerve cord of Caenorhabditis elegans. J Neurosci 19 7048 7056

115. McIntireSLReimerRJSchuskeKEdwardsRHJorgensenEM 1997 Identification and characterization of the vesicular GABA transporter. Nature 389 870 876

116. FireAXuSMontgomeryMKKostasSADriverSE 1998 Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391 806 811

117. TernsRMKroll-ConnerPZhuJChungSRothmanJH 1997 A deficiency screen for zygotic loci required for establishment and patterning of the epidermis in Caenorhabditis elegans. Genetics 146 185 206

118. SulstonJEHodgkinJ 1988 Methods. WoodWB The Nematode Caenorhabditis elegans Cold Spring Harbor Cold Spring Harbor University Press 587 606

119. ChurchDLGuanKLLambieEJ 1995 Three genes of the MAP kinase cascade, mek-2, mpk-1/sur-1 and let-60 ras, are required for meiotic cell cycle progression in Caenorhabditis elegans. Development 121 2525 2535

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