AGEF-1在线虫胞吞作用中的功能研究
|
摘要
胞吞作用是一种囊泡介导的生物途径。细胞无论是从外界环境中吸收营养物质还是更新膜脂膜蛋白,都要依赖于胞吞作用。虽然已经明确了很多蛋白,例如RabGTP酶,在胞吞作用中起到了至关重要的作用,但是对于胞吞作用调控的详细机制研究的并不透彻。大部分研究都集中在胞吞的早期进程,对于胞吞的晚期进程,尤其是溶酶体相关进程还鲜有研究。溶酶体命运的研究不仅对揭示溶酶体相关动力学的调控机制,更对揭示胞吞作用的调控网络具有非常重要的意义。本文利用模式生物秀丽隐杆线虫(Caenorhabditis elegans)对受体介导胞吞作用中的重要调控蛋白AGEF-1的作用机制做了进一步研究,克服了AGEF-1缺失后线虫表现为胚胎致死以及发育停滞不能用于深入研究的难题,利用胚胎后RNAi的方法,在腔胞胞吞作用研究模型中深入研究了AGEF-1对胞吞途径的影响,揭示了AGEF-1在胞吞途径中的新作用。
在线虫中AGEF-1调控卵母细胞对卵黄蛋白的吸收并通过其GEF活性,调控ARF-1/3的活性,影响卵母细胞发育过程中caveolin-1的形成。但迄今为止,AGEF-1的亚细胞定位以及调控胞吞作用的详细机制并不清楚。我们应用含有大量标记的腔胞胞吞作用研究模型,发现AGEF-1的缺失不仅严重影响腔胞对肌肉细胞分泌到假体腔中的可溶性蛋白GFP的吸收,而且腔胞中溶酶体的体积明显增大。进一步研究发现,溶酶体的酸性环境并未改变,水溶性物质胞吞后运输至溶酶体的途径正常,溶酶体的降解功能依然存在,揭示了AGEF-1调控溶酶体的分离/融合过程,但并不调控溶酶体的功能。
基因上位分析表明,AGEF-1于ARL-8蛋白的上游调控内吞的早期过程,又处于ARL-8的下游调控物质向溶酶体的运输以及溶酶体的融合/分离过程。细胞亚定位结果显示AGEF-1定位于溶酶体膜上,表明AGEF-1直接调控着溶酶体相关动力学。对内吞作用早期步骤标记的研究发现AGEF-1在质膜附近调控Clathrin的分布直接调控腔胞对液相物质的内吞。并通过蛋白过表达以及分段蛋白过表达进一步证明了AGEF-1通过结合不同的蛋白或者蛋白复合物调控腔胞内吞液相物质的能力以及腔胞溶酶体形态两个独立事件,且AGEF-1并不依赖ARF-1/3活性调控溶酶体的形态。
总而言之,本论文发现了调控溶酶体融合/分离动力学过程的第一个GTP酶调控因子,对进一步全面深入了解溶酶体相关调控的详细机制以及胞吞作用的整合调控网络具有重要的推动作用。此外AGEF-1在其他组织器官中的功能研究发现,AGEF-1在神经系统中通过调节Clathrin的分布调控神经系统的活性。行为学分析发现AGEF-1缺失后,线虫的爬行速率变慢,泳动速率却变快,揭示了这两种运动行为很可能是由不同的神经环路所控制,为研究Clathrin介导的胞吞作用在神经活动中的功能提供了良好的模型。
The endocytic pathway is a vesicle-mediated process required for various essential cellular functions, including processing fluid and macromolecules from the outside environment, and internalizing plasma membrane lipids and proteins. Although much is known about how some cellular proteins, such as Rab GTPases, regulate some steps of the endocytic pathway, the precise molecular mechanisms are not fully understood, which is especially true for lysosomal transport and dynamics.
Because the endocytic machinery is highly conserved from yeast to mammals, several studies have utilized the worm Caenorhabditis elegans to reveal mechanisms associated with endocytosis in a multicellular organism. We analysed AGEF-1, which is thought to activate classⅠArfs(ARF1-3, small G proteins with long lipid tails function on vecicle traffic and cytoskeleton), endocytic functions in Caenorhabditis elegans coelomocytes. Knockdown of AGEF-1 levels results in two apparent trafficking defects in coelomocytes of Caenorhabditis elegans. First, there is a delay in the uptake of solutes from the extracellular medium. Second, there is a dramatic enlargement of the sizes of lysosomes which is likely the products of homotypic lysosome fusion events, even though lysosomal acidification is normal and degradation still occurs. Our epistasis analysis showed that reduced ARL-8 function abrogates the lysosome defect due to reduced AGEF-1 function, but not the uptake defect. Indeed, early steps of endocytosis analysis showed that after reduced of AGEF-1 levels, the distribution of clathrin at plasma membrane was obviously changed, suggesting that AGEF-1 has a direct role in regulating uptake. Full-length and truncated AGEF-1 proteins overexpressed experiment indicates that AGEF-1 associates with distinct complexs at surface and in endosome/lysosomes.
In conclusion, AGEF-1 is the first identified GTPase regulator that functions at lysosomes fusion/fission stage of the endocytic pathway. Our study sheds light on lysosomal dynamics and endocytosis regulation network. What's more, after reduced of AGEF-1 levels the distribution of clathrin at nervous system was obviously changed. Crawl speed was seriously suppressed, while swimming speed was increased, indicating these two types of locomotion were regulated by different neural circuits. It provides a good model in studing Clathrin-dependent endocytosis functions in maintenance of synaptic vesicle pools.
在线虫中AGEF-1调控卵母细胞对卵黄蛋白的吸收并通过其GEF活性,调控ARF-1/3的活性,影响卵母细胞发育过程中caveolin-1的形成。但迄今为止,AGEF-1的亚细胞定位以及调控胞吞作用的详细机制并不清楚。我们应用含有大量标记的腔胞胞吞作用研究模型,发现AGEF-1的缺失不仅严重影响腔胞对肌肉细胞分泌到假体腔中的可溶性蛋白GFP的吸收,而且腔胞中溶酶体的体积明显增大。进一步研究发现,溶酶体的酸性环境并未改变,水溶性物质胞吞后运输至溶酶体的途径正常,溶酶体的降解功能依然存在,揭示了AGEF-1调控溶酶体的分离/融合过程,但并不调控溶酶体的功能。
基因上位分析表明,AGEF-1于ARL-8蛋白的上游调控内吞的早期过程,又处于ARL-8的下游调控物质向溶酶体的运输以及溶酶体的融合/分离过程。细胞亚定位结果显示AGEF-1定位于溶酶体膜上,表明AGEF-1直接调控着溶酶体相关动力学。对内吞作用早期步骤标记的研究发现AGEF-1在质膜附近调控Clathrin的分布直接调控腔胞对液相物质的内吞。并通过蛋白过表达以及分段蛋白过表达进一步证明了AGEF-1通过结合不同的蛋白或者蛋白复合物调控腔胞内吞液相物质的能力以及腔胞溶酶体形态两个独立事件,且AGEF-1并不依赖ARF-1/3活性调控溶酶体的形态。
总而言之,本论文发现了调控溶酶体融合/分离动力学过程的第一个GTP酶调控因子,对进一步全面深入了解溶酶体相关调控的详细机制以及胞吞作用的整合调控网络具有重要的推动作用。此外AGEF-1在其他组织器官中的功能研究发现,AGEF-1在神经系统中通过调节Clathrin的分布调控神经系统的活性。行为学分析发现AGEF-1缺失后,线虫的爬行速率变慢,泳动速率却变快,揭示了这两种运动行为很可能是由不同的神经环路所控制,为研究Clathrin介导的胞吞作用在神经活动中的功能提供了良好的模型。
The endocytic pathway is a vesicle-mediated process required for various essential cellular functions, including processing fluid and macromolecules from the outside environment, and internalizing plasma membrane lipids and proteins. Although much is known about how some cellular proteins, such as Rab GTPases, regulate some steps of the endocytic pathway, the precise molecular mechanisms are not fully understood, which is especially true for lysosomal transport and dynamics.
Because the endocytic machinery is highly conserved from yeast to mammals, several studies have utilized the worm Caenorhabditis elegans to reveal mechanisms associated with endocytosis in a multicellular organism. We analysed AGEF-1, which is thought to activate classⅠArfs(ARF1-3, small G proteins with long lipid tails function on vecicle traffic and cytoskeleton), endocytic functions in Caenorhabditis elegans coelomocytes. Knockdown of AGEF-1 levels results in two apparent trafficking defects in coelomocytes of Caenorhabditis elegans. First, there is a delay in the uptake of solutes from the extracellular medium. Second, there is a dramatic enlargement of the sizes of lysosomes which is likely the products of homotypic lysosome fusion events, even though lysosomal acidification is normal and degradation still occurs. Our epistasis analysis showed that reduced ARL-8 function abrogates the lysosome defect due to reduced AGEF-1 function, but not the uptake defect. Indeed, early steps of endocytosis analysis showed that after reduced of AGEF-1 levels, the distribution of clathrin at plasma membrane was obviously changed, suggesting that AGEF-1 has a direct role in regulating uptake. Full-length and truncated AGEF-1 proteins overexpressed experiment indicates that AGEF-1 associates with distinct complexs at surface and in endosome/lysosomes.
In conclusion, AGEF-1 is the first identified GTPase regulator that functions at lysosomes fusion/fission stage of the endocytic pathway. Our study sheds light on lysosomal dynamics and endocytosis regulation network. What's more, after reduced of AGEF-1 levels the distribution of clathrin at nervous system was obviously changed. Crawl speed was seriously suppressed, while swimming speed was increased, indicating these two types of locomotion were regulated by different neural circuits. It provides a good model in studing Clathrin-dependent endocytosis functions in maintenance of synaptic vesicle pools.
引文
[1]Dang H, Li Z, Skolnik E Y, et al. Disease-related myotubularins function in endocytic traffic in Caenorhabditis elegans. Mol Biol Cell,2004,15(1):189-196
[2]Fares H, Greenwald I. Regulation of endocytosis by CUP-5, the Caenorhabditis elegans mucolipin-1 homolog. Nat Genet.,2001,28(1):64-68
[3]Conner S D, Schmid S L. Regulated portals of entry into the cell. Nature,2003, 422(6927):37-44
[4]Hall A, Nobes C D. Rho GTPases:molecular switches that control the organization and dynamics of the actin cytoskeleton. Philos Trans R Soc Lond B Biol Sci.,2000, 355(1399):965-970
[5]Razani B, Lisanti M P. Caveolins and caveolae:molecular and functional relationships. Exp Cell Res.,2001,271(1):36-44
[6]Steele-Mortimer O, Knodler L A, Finlay B B. Poisons, ruffles and rockets:bacterial pathogens and the host cell cytoskeleton. Traffic,2000,1(2):107-118
[7]Ridley A J. Rho proteins:linking signaling with membrane trafficking. Traffic, 2001,2(5):303-310
[8]Woodman P G, Warren G. Isolation of functional, coated, endocytic vesicles. J Cell Biol.,1991,112(6):1133-1141
[9]Mayorga L S, Diaz R, Stahl P D. Plasma membrane-derived vesicles containing receptor-ligand complexes are fusogenic with early endosomes in a cell-free system. J Biol Chem.,1988,263(33):17213-17216
[10]Gruenberg J, Howell K. E. An internalized transmembrane protein resides in a fusion-competent endosome for less than 5 minutes. Proc Natl Acad Sci U S A, 1987,84(16):5758-5762
[11]Mukherjee S, Ghosh R N, Maxfield F R. Endocytosis. Physiol Rev.,1997,77(3): 759-803
[12]Grant B D, Sato M. Intracellular trafficking. WormBook,2006:1-9
[13]Aniento F, Emans N, Griffiths G, et al. Cytoplasmic dynein-dependent vesicular transport from early to late endosomes. J Cell Biol.,1993,123(6 Pt 1):1373-1387
[14]Gruenberg J, Griffiths G, Howell K E. Characterization of the early endosome and putative endocytic carrier vesicles in vivo and with an assay of vesicle fusion in vitro. J Cell Biol.,1989,108(4):1301-1316
[15]Dunn K W, Maxfield F R. Delivery of ligands from sorting endosomes to late endosomes occurs by maturation of sorting endosomes. J Cell Biol.,1992,117(2): 301-310
[16]Maxfield F R, Mcgraw T E. Endocytic recycling. Nat Rev Mol Cell Biol.,2004, 5(2):121-132
[17]Poteryaev D, Datta S, Ackema K, et al. Identification of the switch in early-to-late endosome transition. Cell,2010,141(3):497-508
[18]Hunziker W, Geuze H J. Intracellular trafficking of lysosomal membrane proteins. Bioessays,1996,18(5):379-389
[19]Hao M, Maxfield F R. Characterization of rapid membrane internalization and recycling. J Biol Chem.,2000,275(20):15279-15286
[20]Hopkins C R. Intracellular routing of transferrin and transferrin receptors in epidermoid carcinoma A431 cells. Cell,1983,35(1):321-330
[21]Mcgraw T E, Dunn K W, Maxfield F R. Isolation of a temperature-sensitive variant Chinese hamster ovary cell line with a morphologically altered endocytic recycling compartment. J Cell Physiol.,1993,155(3):579-594
[22]Yamashiro D J, Tycko B, Fluss S R, et al. Segregation of transferrin to a mildly acidic (pH 6.5) para-Golgi compartment in the recycling pathway. Cell,1984,37(3): 789-800
[23]Lin S X, Gundersen G G, Maxfield F R. Export from pericentriolar endocytic recycling compartment to cell surface depends on stable, detyrosinated (glu) microtubules and kinesin. Mol Biol Cell,2002,13(1):96-109
[24]Itin C, Rancano C, Nakajima Y, et al. A novel assay reveals a role for soluble N-ethylmaleimide-sensitive fusion attachment protein in mannose 6-phosphate receptor transport from endosomes to the trans Golgi network. J Biol Chem.,1997, 272(44):27737-27744
[25]Presley J F, Mayor S, Mcgraw T E, et al. Bafilomycin Al treatment retards transferrin receptor recycling more than bulk membrane recycling. J Biol Chem., 1997,272(21):13929-13936
[26]Cook N R, Row P E, Davidson H W. Lysosome associated membrane protein 1 (Lampl) traffics directly from the TGN to early endosomes. Traffic,2004,5(9): 685-699
[27]Kawai A, Uchiyama H, Takano S, et al. Autophagosome-lysosome fusion depends on the pH in acidic compartments in CHO cells. Autophagy,2007,3(2):154-157
[28]Bakker A C, Webster P, Jacob W A, et al. Homotypic fusion between aggregated lysosomes triggered by elevated [Ca2+]i in fibroblasts. J Cell Sci.,1997,110 (Pt 18):2227-2238
[29]Luzio J P, Pryor P R, Bright N A. Lysosomes:fusion and function. Nat Rev Mol Cell Biol.,2007,8(8):622-632
[30]Storrie B, Desjardins M. The biogenesis of lysosomes:is it a kiss and run, continuous fusion and fission process?. Bioessays,1996,18(11):895-903
[31]Luzio J P, Rous B A, Bright N A, et al. Lysosome-endosome fusion and lysosome biogenesis. J Cell Sci.,2000,113 (Pt 9):1515-1524
[32]Luzio J P, Parkinson M D, Gray S R, et al. The delivery of endocytosed cargo to lysosomes. Biochem Soc Trans.,2009,37(Pt 5):1019-1021
[33]Murphy R F. Maturation models for endosome and lysosome biogenesis. Trends Cell Biol.,1991,1(4):77-82
[34]Dell'Angelica E C, Mullins C, Caplan S, et al. Lysosome-related organelles. FASEB J.,2000,14(10):1265-1278
[35]Mullins C, Bonifacino J S. The molecular machinery for lysosome biogenesis. Bioessays,2001,23(4):333-343
[36]Rothman J E, Sollner T H. Throttles and dampers:controlling the engine of membrane fusion. Science,1997,276(5316):1212-1213
[37]Zerial M, Mcbride H. Rab proteins as membrane organizers. Nat Rev Mol Cell Biol., 2001,2(2):107-117
[38]Somsel R J, Wandinger-Ness A. Rab GTPases coordinate endocytosis. J Cell Sci., 2000,113 Pt 2:183-192
[39]Horiuchi H, Lippe R, Mcbride H M, et al. A novel Rab5 GDP/GTP exchange factor complexed to Rabaptin-5 links nucleotide exchange to effector recruitment and function. Cell,1997,90(6):1149-1159
[40]Xiao G H, Shoarinejad F, Jin F, et al. The tuberous sclerosis 2 gene product, tuberin, functions as a Rab5 GTPase activating protein (GAP) in modulating endocytosis. J Biol Chem.,1997,272(10):6097-6100
[41]Pfeffer S R, Dirac-Svejstrup A B, Soldati T. Rab GDP dissociation inhibitor:putting rab GTPases in the right place. J Biol Chem.,1995,270(29):17057-17059
[42]Dirac-Svejstrup A B, Sumizawa T, Pfeffer S R. Identification of a GDI displacement factor that releases endosomal Rab GTPases from Rab-GDI. EMBO J., 1997,16(3):465-472
[43]Simonsen A, Lippe R, Christoforidis S, et al. EEA1 links PI(3)K function to Rab5 regulation of endosome fusion. Nature,1998,394(6692):494-498
[44]Barbieri M A, Hoffenberg S, Roberts R, et al. Evidence for a symmetrical requirement for Rab5-GTP in in vitro endosome-endosome fusion. J Biol Chem., 1998,273(40):25850-25855
[45]Rubino M, Miaczynska M, Lippe R, et al. Selective membrane recruitment of EEA1 suggests a role in directional transport of clathrin-coated vesicles to early endosomes. J Biol Chem.,2000,275(6):3745-3748
[46]Bananis E, Murray J W, Stockert R J, et al. Regulation of early endocytic vesicle motility and fission in a reconstituted system. J Cell Sci.,2003,116(Pt 13): 2749-2761
[47]Wilcke M, Johannes L, Galli T, et al. Rab11 regulates the compartmentalization of early endosomes required for efficient transport from early endosomes to the trans-golgi network. J Cell Biol.,2000,151(6):1207-1220
[48]Ren M, Xu G, Zeng J, et al. Hydrolysis of GTP on rabl 1 is required for the direct delivery of transferrin from the pericentriolar recycling compartment to the cell surface but not from sorting endosomes. Proc Natl Acad Sci U S A,1998,95(11): 6187-6192
[49]Barbero P, Bittova L, Pfeffer S R. Visualization of Rab9-mediated vesicle transport from endosomes to the trans-Golgi in living cells. J Cell Biol.,2002,156(3): 511-518
[50]Rink J, Ghigo E, Kalaidzidis Y, et al. Rab conversion as a mechanism of progression from early to late endosomes. Cell,2005,122(5):735-749
[51]Van Der Sluijs P, Hull M, Zahraoui A, et al. The small GTP-binding protein rab4 is associated with early endosomes. Proc Natl Acad Sci U S A,1991,88(14): 6313-6317
[52]Lutcke A, Parton R G, Murphy C, et al. Cloning and subcellular localization of novel rab proteins reveals polarized and cell type-specific expression. J Cell Sci., 1994,107 (Pt 12):3437-3448
[53]Bucci C, Lutcke A, Steele-Mortimer O, et al. Co-operative regulation of endocytosis by three Rab5 isoforms. FEBS Lett.,1995,366(1):65-71
[54]Ullrich O, Reinsch S, Urbe S, et al. Rab11 regulates recycling through the pericentriolar recycling endosome. J Cell Biol.,1996,135(4):913-924
[55]Green E G, Ramm E, Riley N M, et al. Rab11 is associated with transferrin-containing recycling compartments in K562 cells. Biochem Biophys Res Commun.,1997,239(2):612-616
[56]Casanova J E, Wang X, Kumar R, et al. Association of Rab25 and Rab11a with the apical recycling system of polarized Madin-Darby canine kidney cells. Mol Biol Cell,1999,10(1):47-61
[57]Bucci C, Thomsen P, Nicoziani P, et al. Rab7:a key to lysosome biogenesis. Mol Biol Cell,2000,11(2):467-480
[58]Meresse S, Gorvel J P, Chavrier P. The rab7 GTPase resides on a vesicular compartment connected to lysosomes. J Cell Sci.,1995,108 (Pt 11):3349-3358
[59]von Mollard G F, Nothwehr S F, Stevens T H. The yeast v-SNARE Vtilp mediates two vesicle transport pathways through interactions with the t-SNAREs Sed5p and Pep12p. J Cell Biol.,1997,137(7):1511-1524
[60]Holthuis J C, Nichols B J, Dhruvakumar S, et al. Two syntaxin homologues in the TGN/endosomal system of yeast. EMBO J.,1998,17(1):113-126
[61]Fasshauer D, Antonin W, Margittai M, et al. Mixed and non-cognate SNARE complexes. Characterization of assembly and biophysical properties. J Biol Chem., 1999,274(22):15440-15446
[62]Yang B, Gonzalez L J, Prekeris R, et al. SNARE interactions are not selective. Implications for membrane fusion specificity. J Biol Chem.,1999,274(9): 5649-5653
[63]Hickey C M, Wickner W. HOPS initiates vacuole docking by tethering membranes before trans-SNARE complex assembly. Mol Biol Cell,2010,21(13):2297-2305
[64]Sun Q, Westphal W, Wong K N, et al. Rubicon controls endosome maturation as a Rab7 effector. Proc Natl Acad Sci U S A,2010,107(45):19338-19343
[65]Antonin W, Holroyd C, Fasshauer D, et al. A SNARE complex mediating fusion of late endosomes defines conserved properties of SNARE structure and function. EMBO J.,2000,19(23):6453-6464
[66]Hay J C. SNARE complex structure and function. Exp Cell Res.2001,271(1): 10-21
[67]Sternberg P W. Working in the post-genomic C. elegans world. Cell,2001,105(2): 173-176
[68]Grant B, Hirsh D. Receptor-mediated endocytosis in the Caenorhabditis elegans oocyte. Mol Biol Cell,1999,10(12):4311-4326
[69]Grant B, Zhang Y, Paupard M C, et al. Evidence that RME-1, a conserved C. elegans EH-domain protein, functions in endocytic recycling. Nat Cell Biol.,2001, 3(6):573-579
[70]Zhang Y, Grant B, Hirsh D. RME-8, a conserved J-domain protein, is required for endocytosis in Caenorhabditis elegans. Mol Biol Cell,2001,12(7):2011-2021
[71]Treusch S, Knuth S, Slaugenhaupt S A, et al. Caenorhabditis elegans functional orthologue of human protein h-mucolipin-1 is required for lysosome biogenesis. Proc Natl Acad Sci U S A,2004,101(13):4483-4488
[72]Jones A K, Sattelle D B. Functional genomics of the nicotinic acetylcholine receptor gene family of the nematode, Caenorhabditis elegans. Bioessays,2004,26(1): 39-49
[73]Patton A, Knuth S, Schaheen B, et al. Endocytosis function of a ligand-gated ion channel homolog in Caenorhabditis elegans. Curr Biol.,2005,15(11):1045-1050
[74]Bagshaw R D, Callahan J W, Mahuran D J. The Arf-family protein, Ar18b, is involved in the spatial distribution of lysosomes. Biochem Biophys Res Commun., 2006,344(4):1186-1191
[75]Hofmann I, Munro S. An N-terminally acetylated Arf-like GTPase is localised to lysosomes and affects their motility. J Cell Sci.,2006,119(Pt 8):1494-1503
[76]Nakae I, Fujino T, Kobayashi T, et al. The arf-like GTPase Ar18 mediates delivery of endocytosed macromolecules to lysosomes in Caenorhabditis elegans. Mol Biol Cell,2010,21(14):2434-2442
[77]Fire A, Xu S, Montgomery M K, et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature,1998,391(6669):806-811
[78]Winston W M, Molodowitch C, Hunter C P. Systemic RNAi in C. elegans requires the putative transmembrane protein SID-1. Science,2002,295(5564):2456-2459
[79]Guo S, Kemphues K J. par-1, a gene required for establishing polarity in C. elegans embryos, encodes a putative Ser/Thr kinase that is asymmetrically distributed. Cell, 1995,81(4):611-620
[80]Maine E M. RNAi As a tool for understanding germline development in Caenorhabditis elegans:uses and cautions. Dev Biol.,2001,239(2):177-189
[81]Sharp P A, Zamore P D. Molecular biology. RNA interference. Science,2000, 287(5462):2431-2433
[82]Tchurikov N A, Chistyakova L G, Zavilgelsky G B, et al. Gene-specific silencing by expression of parallel complementary RNA in Escherichia coli. J Biol Chem., 2000,275(34):26523-26529
[83]Kamath R S, Martinez-Campos M, Zipperlen P, et al. Effectiveness of specific RNA-mediated interference through ingested double-stranded RNA in Caenorhabditis elegans. Genome Biol.,2001,2(1):H2
[84]Piatkevich K D, Verkhusha V V. Advances in engineering of fluorescent proteins and photoactivatable proteins with red emission. Curr Opin Chem Biol.,2010,14(1): 23-29
[85]Day R N, Davidson M W. The fluorescent protein palette:tools for cellular imaging. Chem Soc Rev.,2009,38(10):2887-2921
[86]Boulin T, Etchberger J F, Hobert O. Reporter gene fusions. WormBook,2006:1-23
[87]Teramoto T, Iwasaki K. Intestinal calcium waves coordinate a behavioral motor program in C. elegans. Cell Calcium.,2006,40(3):319-327
[88]酒亚明,张蓉颖,吴政星.线虫基因显微注射和整合技术——设备、操作与指南.生物化学与生物物理进展,2009,36(5)：648-652
[89]Tsuchiya M, Price S R, Tsai S C, et al. Molecular identification of ADP-ribosylation factor mRNAs and their expression in mammalian cells. J Biol Chem.,1991,266(5): 2772-2777
[90]Kumari S, Mayor S. ARF1 is directly involved in dynamin-independent endocytosis. Nat Cell Biol.,2008,10(1):30-41
[91]Kostich M, Fire A, Fambrough D M. Identification and molecular-genetic characterization of a LAMP/CD68-like protein from Caenorhabditis elegans. J Cell Sci.,2000,113 (Pt 14):2595-2606
[92]Jackson C L, Casanova J E. Turning on ARF:the Sec7 family of guanine-nucleotide-exchange factors. Trends Cell Biol.,2000,10(2):60-67
[93]Sato K, Sato M, Audhya A, et al. Dynamic regulation of caveolin-1 trafficking in the germ line and embryo of Caenorhabditis elegans. Mol Biol Cell,2006,17(7): 3085-3094
[94]Balklava Z, Pant S, Fares H, et al. Genome-wide analysis identifies a general requirement for polarity proteins in endocytic traffic. Nat Cell Biol.,2007,9(9): 1066-1073
[95]Greener T, Grant B, Zhang Y, et al. Caenorhabditis elegans auxilin:a J-domain protein essential for clathrin-mediated endocytosis in vivo. Nat Cell Biol.,2001, 3(2):215-219
[96]Nilsson L, Conradt B, Ruaud A F, et al. Caenorhabditis elegans num-1 negatively regulates endocytic recycling. Genetics,2008,179(1):375-387
[97]Fares H, Greenwald I. Genetic analysis of endocytosis in Caenorhabditis elegans: coelomocyte uptake defective mutants. Genetics,2001,159(1):133-145
[98]Brenner S. The genetics of Caenorhabditis elegans. Genetics.1974,77(1):71-94
[99]Lu Q, Zhang Y, Hu T, et al. C. elegans Rab GTPase 2 is required for the degradation of apoptotic cells. Development,2008,135(6):1069-1080
[100]Poteryaev D, Fares H, Bowerman B, et al. Caenorhabditis elegans SAND-1 is essential for RAB-7 function in endosomal traffic. EMBO J.,2007,26(2):301-312
[101]Bednarek E M, Schaheen L, Gaubatz J, et al. The plasma membrane calcium ATPase MCA-3 is required for clathrin-mediated endocytosis in scavenger cells of Caenorhabditis elegans. Traffic,2007,8(5):543-553
[102]Nicot A S, Fares H, Payrastre B, et al. The phosphoinositide kinase PIKfyve/Fablp regulates terminal lysosome maturation in Caenorhabditis elegans. Mol Biol Cell, 2006,17(7):3062-3074
[103]Li Y, Kelly W G, Logsdon J J, et al. Functional genomic analysis of the ADP-ribosylation factor family of GTPases:phylogeny among diverse eukaryotes and function in C. elegans. FASEB J.,2004,18(15):1834-1850
[104]Simmer F, Moorman C, van der Linden A M, et al. Genome-wide RNAi of C. elegans using the hypersensitive rrf-3 strain reveals novel gene functions. PLoS Biol.,2003,1(1):E12
[105]Lin S X, Grant B, Hirsh D, et al. Rme-1 regulates the distribution and function of the endocytic recycling compartment in mammalian cells. Nat Cell Biol.,2001,3(6): 567-572
[106]Hersh B M, Hartwieg E, Horvitz H R. The Caenorhabditis elegans mucolipin-like gene cup-5 is essential for viability and regulates lysosomes in multiple cell types. Proc Natl Acad Sci U S A,2002,99(7):4355-4360
[107]Piper R C, Luzio J P. CUPpling calcium to lysosomal biogenesis. Trends Cell Biol., 2004,14(9):471-473
[108]Vonderheit A, Helenius A. Rab7 associates with early endosomes to mediate sorting and transport of Semliki forest virus to late endosomes. PLoS Biol.,2005,3(7): e233
[109]Tischler J, Lehner B, Chen N, et al. Combinatorial RNA interference in Caenorhabditis elegans reveals that redundancy between gene duplicates can be maintained for more than 80 million years of evolution. Genome Biol.,2006,7(8): R69
[110]Gouda K, Matsunaga Y, Iwasaki T, et al. An altered method of feeding RNAi that knocks down multiple genes simultaneously in the nematode Caenorhabditis elegans. Biosci Biotechnol Biochem.,2010,74(11):2361-2365
[111]Luo L, Hannemann M, Koenig S, et al. The Caenorhabditis elegans GARP complex contains the conserved Vps51 subunit and is required to maintain lysosomal morphology. Mol Biol Cell,2011,22(14):2564-2578
[112]Gaidarov I, Keen J H. Phosphoinositide-AP-2 interactions required for targeting to plasma membrane clathrin-coated pits. J Cell Biol.,1999,146(4):755-764
[113]Ford M G, Pearse B M, Higgins M K, et al. Simultaneous binding of Ptdlns(4,5)P2 and clathrin by AP180 in the nucleation of clathrin lattices on membranes. Science, 2001,291(5506):1051-1055
[114]Sato K, Ernstrom G G, Watanabe S, et al. Differential requirements for clathrin in receptor-mediated endocytosis and maintenance of synaptic vesicle pools. Proc Natl Acad Sci U S A.2009,106(4):1139-1144
[115]陈大华,叶和春,李国凤等.绿色荧光蛋白基因在青蒿转基因芽中的表达.植物学报,1999,41(5)：490
[116]Norbury C C. Drinking a lot is good for dendritic cells. Immunology,2006,117(4): 443-451
[117]Foster F M, Traer C J, Abraham S M, et al. The phosphoinositide (PI) 3-kinase family. J Cell Sci.,2003,116(Pt 15):3037-3040
[118]Backer J M. The regulation and function of Class Ⅲ PI3Ks:novel roles for Vps34. Biochem J.,2008,410(1):1-17
[119]Vieira O V, Botelho R J, Rameh L, et al. Distinct roles of class Ⅰ and class Ⅲ phosphatidylinositol 3-kinases in phagosome formation and maturation. J Cell Biol., 2001,155(1):19-25
[120]Christoforidis S, Mcbride H M, Burgoyne R D, et al. The Rab5 effector EEA1 is a core component of endosome docking. Nature,1999,397(6720):621-625
[121]Stein M P, Feng Y, Cooper K L, et al. Human VPS34 and p150 are Rab7 interacting partners. Traffic,2003,4(11):754-771
[122]Chardin P, Paris S, Antonny B, et al. A human exchange factor for ARF contains Sec7-and pleckstrin-homology domains. Nature,1996,384(6608):481-484
[123]Robinson M S, Watts C, Zerial M. Membrane dynamics in endocytosis. Cell,1996, 84(1):13-21
[124]Gruenberg J, Maxfield F R. Membrane transport in the endocytic pathway. Curr Opin Cell Biol.,1995,7(4):552-563
[125]Pfeffer S R. Rab GTPases:master regulators of membrane trafficking. Curr Opin Cell Biol.,1994,6(4):522-526
[126]Lombardi D, Soldati T, Riederer M A, et al. Rab9 functions in transport between late endosomes and the trans Golgi network. EMBO J.,1993,12(2):677-682
[127]Laurent O, Bruckert F, Adessi C, et al. In vitro reconstituted Dictyostelium discoideum early endosome fusion is regulated by Rab7 but proceeds in the absence of ATP-Mg2+from the bulk solution. J Biol Chem.,1998,273(2):793-799
[128]Mills I G, Jones A T, Clague M J. Involvement of the endosomal autoantigen EEA1 in homotypic fusion of early endosomes. Curr Biol.,1998,8(15):881-884
[129]Mayer A, Wickner W, Haas A. Secl8p (NSF)-driven release of Secl7p (alpha-SNAP) can precede docking and fusion of yeast vacuoles. Cell,1996,85(1): 83-94
[130]Haas A, Scheglmann D, Lazar T, et al. The GTPase Ypt7p of Saccharomyces cerevisiae is required on both partner vacuoles for the homotypic fusion step of vacuole inheritance. EMBO J.,1995,14(21):5258-5270
[131]Tian Y, Li Z, Hu W, et al. C. elegans screen identifies autophagy genes specific to multicellular organisms. Cell,2010,141(6):1042-1055
[132]Duncan R, Pratten M K. Membrane economics in endocytic systems. J Theor Biol., 1977,66(4):727-735
[133]Toth M L, Simon P, Kovacs A L, et al. Influence of autophagy genes on ion-channel-dependent neuronal degeneration in Caenorhabditis elegans. J Cell Sci., 2007,120(Pt6):1134-1141
[134]Nonet M L. Visualization of synaptic specializations in live C. elegans with synaptic vesicle protein-GFP fusions. J Neurosci Methods,1999,89(1):33-40
[135]Sakamoto R, Byrd D T, Brown H M, et al. The Caenorhabditis elegans UNC-14 RUN domain protein binds to the kinesin-1 and UNC-16 complex and regulates synaptic vesicle localization. Mol Biol Cell,2005,16(2):483-496
[136]Sato M, Sato K, Fonarev P, et al. Caenorhabditis elegans RME-6 is a novel regulator of RAB-5 at the clathrin-coated pit. Nat Cell Biol.,2005,7(6):559-569
[137]Chen C C, Schweinsberg P J, Vashist S, et al. RAB-10 is required for endocytic recycling in the Caenorhabditis elegans intestine. Mol Biol Cell,2006,17(3): 1286-1297
[138]Clokey G V, Jacobson L A. The autofluorescent "lipofuscin granules" in the intestinal cells of Caenorhabditis elegans are secondary lysosomes. Mech Ageing Dev.,1986,35(1):79-94
[139]Hermann G J, Schroeder L K, Hieb C A, et al. Genetic analysis of lysosomal trafficking in Caenorhabditis elegans. Mol Biol Cell,2005,16(7):3273-3288
[140]Ashrafi K, Chang F Y, Watts J L, et al. Genome-wide RNAi analysis of Caenorhabditis elegans fat regulatory genes. Nature,2003,421(6920):268-272
[141]Hansen M, Chandra A, Mitic L L, et al. A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS Genet.,2008,4(2):e24
[142]Melendez A, Talloczy Z, Seaman M, et al. Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science,2003,301(5638): 1387-1391
[143]Spanier B, Sturzenbaum S R, Holden-Dye L M, et al. Caenorhabditis elegans neprilysin NEP-1:an effector of locomotion and pharyngeal pumping. J Mol Biol., 2005,352(2):429-437
[144]Chiang J T, Steciuk M, Shtonda B, et al. Evolution of pharyngeal behaviors and neuronal functions in free-living soil nematodes. J Exp Biol.,2006,209(Pt 10): 1859-1873
[145]Dal Santo P, Logan M A, Chisholm A D, et al. The inositol trisphosphate receptor regulates a 50-second behavioral rhythm in C. elegans. Cell,1999,98(6):757-767
[146]Mesce K A, Pierce-Shimomura J T. Shared Strategies for Behavioral Switching: Understanding How Locomotor Patterns are Turned on and Off. Front Behav Neurosci.,2010,4
[147]Pierce-Shimomura J T, Chen B L, Mun J J, et al. Genetic analysis of crawling and swimming locomotory patterns in C. elegans. Proc Natl Acad Sci U S A,2008, 105(52):20982-20987
[148]Berri S, Boyle J H, Tassieri M, et al. Forward locomotion of the nematode C. elegans is achieved through modulation of a single gait. HFSP J.,2009,3(3): 186-193
[149]Boyle J H, Berri S, Tassieri M, et al. Gait Modulation in C. elegans:It's Not a Choice, It's a Reflex!. Front Behav Neurosci.,2011,5:10
[150]Vidal-Gadea A, Topper S, Young L, et al. Caenorhabditis elegans selects distinct crawling and swimming gaits via dopamine and serotonin. Proc Natl Acad Sci U S A,2011,108(42):17504-17509
[151]Zhao H, Nonet M L. A retrograde signal is involved in activity-dependent remodeling at a C. elegans neuromuscular junction. Development,2000,127(6): 1253-1266
[152]Mcewen J M, Madison J M, Dybbs M, et al. Antagonistic regulation of synaptic vesicle priming by Tomosyn and UNC-13. Neuron.,2006,51(3):303-315
[153]Goodman M B, Hall D H, Avery L, et al. Active currents regulate sensitivity and dynamic range in C. elegans neurons. Neuron.,1998,20(4):763-772
[154]Kerr R, Lev-Ram V, Baird G, et al. Optical imaging of calcium transients in neurons and pharyngeal muscle of C. elegans. Neuron.,2000,26(3):583-594
[155]Clark D A, Biron D, Sengupta P, et al. The AFD sensory neurons encode multiple functions underlying thermotactic behavior in Caenorhabditis elegans. J Neurosci., 2006,26(28):7444-7451
[156]Zeng F, Rohde C B, Yanik M F. Sub-cellular precision on-chip small-animal immobilization, multi-photon imaging and femtosecond-laser manipulation. Lab Chip,2008,8(5):653-656
[157]Lewis J A, Wu C H, Berg H, et al. The genetics of levamisole resistance in the nematode Caenorhabditis elegans. Genetics,1980,95(4):905-928
[158]Mccarter J, Bartlett B, Dang T, et al. On the control of oocyte meiotic maturation and ovulation in Caenorhabditis elegans. Dev Biol.,1999,205(1):111-128
[159]Wu Z, Ghosh-Roy A, Yanik M F, et al. Caenorhabditis elegans neuronal regeneration is influenced by life stage, ephrin signaling, and synaptic branching. Proc Natl Acad Sci U S A,2007,104(38):15132-15137
[160]Norris A D, Dyer J O, Lundquist E A. The Arp2/3 complex, UNC-115/abLIM, and UNC-34/Enabled regulate axon guidance and growth cone filopodia formation in Caenorhabditis elegans. Neural Dev.,2009,4:38
[161]Ghosh R, Emmons S W. Episodic swimming behavior in the nematode C. elegans. J Exp Biol.,2008,211(Pt 23):3703-3711
[162]Richmond J E, Jorgensen E M. One GABA and two acetylcholine receptors function at the C. elegans neuromuscular junction. Nat Neurosci.,1999,2(9): 791-797
[163]Chung K, Crane M M, Lu H. Automated on-chip rapid microscopy, phenotyping and sorting of C. elegans. Nat Methods,2008,5(7):637-643
[164]Chokshi T V, Ben-Yakar A, Chronis N. CO2 and compressive immobilization of C. elegans on-chip. Lab Chip,2009,9(1):151-157
[165]Rohde C B, Zeng F, Gonzalez-Rubio R, et al. Microfluidic system for on-chip high-throughput whole-animal sorting and screening at subcellular resolution. Proc Natl Acad Sci U S A,2007,104(35):13891-13895
[166]Allen P B, Sgro A E, Chao D L, et al. Single-synapse ablation and long-term imaging in live C. elegans. J Neurosci Methods,2008,173(1):20-26
[167]Hulme S E, Shevkoplyas S S, Apfeld J, et al. A microfabricated array of clamps for immobilizing and imaging C. elegans. Lab Chip,2007,7(11):1515-1523
[168]Hulme S E, Shevkoplyas S S, Mcguigan A P, et al. Lifespan-on-a-chip:microfluidic chambers for performing lifelong observation of C. elegans. Lab Chip,2010,10(5): 589-597
[169]Mcdonald J C, Duffy D C, Anderson J R, et al. Fabrication of microfluidic systems in poly(dimethylsiloxane). Electrophoresis,2000,21(1):27-40
[170]Duffy D C, Mcdonald J C, Schueller O J, et al. Rapid Prototyping of Microfluidic Systems in Poly(dimethylsiloxane). Anal Chem.,1998,70(23):4974-4984
[171]Henderson S T, Johnson T E. daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans. Curr Biol.,2001, 11(24):1975-1980
[172]Lin K, Hsin H, Libina N, et al. Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling. Nat Genet.,2001,28(2): 139-145
[173]Ogg S, Paradis S, Gottlieb S, et al. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature,1997, 389(6654):994-999
[174]Johnson T E, Mitchell D H, Kline S, et al. Arresting development arrests aging in the nematode Caenorhabditis elegans. Mech Ageing Dev.,1984,28(1):23-40
[175]Paradis S, Ailion M, Toker A, et al. A PDK1 homolog is necessary and sufficient to transduce AGE-1 PI3 kinase signals that regulate diapause in Caenorhabditis elegans. Genes Dev.,1999,13(11):1438-1452
[176]Lin K, Dorman J B, Rodan A, et al. daf-16:An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Science,1997, 278(5341):1319-1322
[177]Murakami S, Johnson T E. A genetic pathway conferring life extension and resistance to UV stress in Caenorhabditis elegans. Genetics,1996,143(3): 1207-1218
[2]Fares H, Greenwald I. Regulation of endocytosis by CUP-5, the Caenorhabditis elegans mucolipin-1 homolog. Nat Genet.,2001,28(1):64-68
[3]Conner S D, Schmid S L. Regulated portals of entry into the cell. Nature,2003, 422(6927):37-44
[4]Hall A, Nobes C D. Rho GTPases:molecular switches that control the organization and dynamics of the actin cytoskeleton. Philos Trans R Soc Lond B Biol Sci.,2000, 355(1399):965-970
[5]Razani B, Lisanti M P. Caveolins and caveolae:molecular and functional relationships. Exp Cell Res.,2001,271(1):36-44
[6]Steele-Mortimer O, Knodler L A, Finlay B B. Poisons, ruffles and rockets:bacterial pathogens and the host cell cytoskeleton. Traffic,2000,1(2):107-118
[7]Ridley A J. Rho proteins:linking signaling with membrane trafficking. Traffic, 2001,2(5):303-310
[8]Woodman P G, Warren G. Isolation of functional, coated, endocytic vesicles. J Cell Biol.,1991,112(6):1133-1141
[9]Mayorga L S, Diaz R, Stahl P D. Plasma membrane-derived vesicles containing receptor-ligand complexes are fusogenic with early endosomes in a cell-free system. J Biol Chem.,1988,263(33):17213-17216
[10]Gruenberg J, Howell K. E. An internalized transmembrane protein resides in a fusion-competent endosome for less than 5 minutes. Proc Natl Acad Sci U S A, 1987,84(16):5758-5762
[11]Mukherjee S, Ghosh R N, Maxfield F R. Endocytosis. Physiol Rev.,1997,77(3): 759-803
[12]Grant B D, Sato M. Intracellular trafficking. WormBook,2006:1-9
[13]Aniento F, Emans N, Griffiths G, et al. Cytoplasmic dynein-dependent vesicular transport from early to late endosomes. J Cell Biol.,1993,123(6 Pt 1):1373-1387
[14]Gruenberg J, Griffiths G, Howell K E. Characterization of the early endosome and putative endocytic carrier vesicles in vivo and with an assay of vesicle fusion in vitro. J Cell Biol.,1989,108(4):1301-1316
[15]Dunn K W, Maxfield F R. Delivery of ligands from sorting endosomes to late endosomes occurs by maturation of sorting endosomes. J Cell Biol.,1992,117(2): 301-310
[16]Maxfield F R, Mcgraw T E. Endocytic recycling. Nat Rev Mol Cell Biol.,2004, 5(2):121-132
[17]Poteryaev D, Datta S, Ackema K, et al. Identification of the switch in early-to-late endosome transition. Cell,2010,141(3):497-508
[18]Hunziker W, Geuze H J. Intracellular trafficking of lysosomal membrane proteins. Bioessays,1996,18(5):379-389
[19]Hao M, Maxfield F R. Characterization of rapid membrane internalization and recycling. J Biol Chem.,2000,275(20):15279-15286
[20]Hopkins C R. Intracellular routing of transferrin and transferrin receptors in epidermoid carcinoma A431 cells. Cell,1983,35(1):321-330
[21]Mcgraw T E, Dunn K W, Maxfield F R. Isolation of a temperature-sensitive variant Chinese hamster ovary cell line with a morphologically altered endocytic recycling compartment. J Cell Physiol.,1993,155(3):579-594
[22]Yamashiro D J, Tycko B, Fluss S R, et al. Segregation of transferrin to a mildly acidic (pH 6.5) para-Golgi compartment in the recycling pathway. Cell,1984,37(3): 789-800
[23]Lin S X, Gundersen G G, Maxfield F R. Export from pericentriolar endocytic recycling compartment to cell surface depends on stable, detyrosinated (glu) microtubules and kinesin. Mol Biol Cell,2002,13(1):96-109
[24]Itin C, Rancano C, Nakajima Y, et al. A novel assay reveals a role for soluble N-ethylmaleimide-sensitive fusion attachment protein in mannose 6-phosphate receptor transport from endosomes to the trans Golgi network. J Biol Chem.,1997, 272(44):27737-27744
[25]Presley J F, Mayor S, Mcgraw T E, et al. Bafilomycin Al treatment retards transferrin receptor recycling more than bulk membrane recycling. J Biol Chem., 1997,272(21):13929-13936
[26]Cook N R, Row P E, Davidson H W. Lysosome associated membrane protein 1 (Lampl) traffics directly from the TGN to early endosomes. Traffic,2004,5(9): 685-699
[27]Kawai A, Uchiyama H, Takano S, et al. Autophagosome-lysosome fusion depends on the pH in acidic compartments in CHO cells. Autophagy,2007,3(2):154-157
[28]Bakker A C, Webster P, Jacob W A, et al. Homotypic fusion between aggregated lysosomes triggered by elevated [Ca2+]i in fibroblasts. J Cell Sci.,1997,110 (Pt 18):2227-2238
[29]Luzio J P, Pryor P R, Bright N A. Lysosomes:fusion and function. Nat Rev Mol Cell Biol.,2007,8(8):622-632
[30]Storrie B, Desjardins M. The biogenesis of lysosomes:is it a kiss and run, continuous fusion and fission process?. Bioessays,1996,18(11):895-903
[31]Luzio J P, Rous B A, Bright N A, et al. Lysosome-endosome fusion and lysosome biogenesis. J Cell Sci.,2000,113 (Pt 9):1515-1524
[32]Luzio J P, Parkinson M D, Gray S R, et al. The delivery of endocytosed cargo to lysosomes. Biochem Soc Trans.,2009,37(Pt 5):1019-1021
[33]Murphy R F. Maturation models for endosome and lysosome biogenesis. Trends Cell Biol.,1991,1(4):77-82
[34]Dell'Angelica E C, Mullins C, Caplan S, et al. Lysosome-related organelles. FASEB J.,2000,14(10):1265-1278
[35]Mullins C, Bonifacino J S. The molecular machinery for lysosome biogenesis. Bioessays,2001,23(4):333-343
[36]Rothman J E, Sollner T H. Throttles and dampers:controlling the engine of membrane fusion. Science,1997,276(5316):1212-1213
[37]Zerial M, Mcbride H. Rab proteins as membrane organizers. Nat Rev Mol Cell Biol., 2001,2(2):107-117
[38]Somsel R J, Wandinger-Ness A. Rab GTPases coordinate endocytosis. J Cell Sci., 2000,113 Pt 2:183-192
[39]Horiuchi H, Lippe R, Mcbride H M, et al. A novel Rab5 GDP/GTP exchange factor complexed to Rabaptin-5 links nucleotide exchange to effector recruitment and function. Cell,1997,90(6):1149-1159
[40]Xiao G H, Shoarinejad F, Jin F, et al. The tuberous sclerosis 2 gene product, tuberin, functions as a Rab5 GTPase activating protein (GAP) in modulating endocytosis. J Biol Chem.,1997,272(10):6097-6100
[41]Pfeffer S R, Dirac-Svejstrup A B, Soldati T. Rab GDP dissociation inhibitor:putting rab GTPases in the right place. J Biol Chem.,1995,270(29):17057-17059
[42]Dirac-Svejstrup A B, Sumizawa T, Pfeffer S R. Identification of a GDI displacement factor that releases endosomal Rab GTPases from Rab-GDI. EMBO J., 1997,16(3):465-472
[43]Simonsen A, Lippe R, Christoforidis S, et al. EEA1 links PI(3)K function to Rab5 regulation of endosome fusion. Nature,1998,394(6692):494-498
[44]Barbieri M A, Hoffenberg S, Roberts R, et al. Evidence for a symmetrical requirement for Rab5-GTP in in vitro endosome-endosome fusion. J Biol Chem., 1998,273(40):25850-25855
[45]Rubino M, Miaczynska M, Lippe R, et al. Selective membrane recruitment of EEA1 suggests a role in directional transport of clathrin-coated vesicles to early endosomes. J Biol Chem.,2000,275(6):3745-3748
[46]Bananis E, Murray J W, Stockert R J, et al. Regulation of early endocytic vesicle motility and fission in a reconstituted system. J Cell Sci.,2003,116(Pt 13): 2749-2761
[47]Wilcke M, Johannes L, Galli T, et al. Rab11 regulates the compartmentalization of early endosomes required for efficient transport from early endosomes to the trans-golgi network. J Cell Biol.,2000,151(6):1207-1220
[48]Ren M, Xu G, Zeng J, et al. Hydrolysis of GTP on rabl 1 is required for the direct delivery of transferrin from the pericentriolar recycling compartment to the cell surface but not from sorting endosomes. Proc Natl Acad Sci U S A,1998,95(11): 6187-6192
[49]Barbero P, Bittova L, Pfeffer S R. Visualization of Rab9-mediated vesicle transport from endosomes to the trans-Golgi in living cells. J Cell Biol.,2002,156(3): 511-518
[50]Rink J, Ghigo E, Kalaidzidis Y, et al. Rab conversion as a mechanism of progression from early to late endosomes. Cell,2005,122(5):735-749
[51]Van Der Sluijs P, Hull M, Zahraoui A, et al. The small GTP-binding protein rab4 is associated with early endosomes. Proc Natl Acad Sci U S A,1991,88(14): 6313-6317
[52]Lutcke A, Parton R G, Murphy C, et al. Cloning and subcellular localization of novel rab proteins reveals polarized and cell type-specific expression. J Cell Sci., 1994,107 (Pt 12):3437-3448
[53]Bucci C, Lutcke A, Steele-Mortimer O, et al. Co-operative regulation of endocytosis by three Rab5 isoforms. FEBS Lett.,1995,366(1):65-71
[54]Ullrich O, Reinsch S, Urbe S, et al. Rab11 regulates recycling through the pericentriolar recycling endosome. J Cell Biol.,1996,135(4):913-924
[55]Green E G, Ramm E, Riley N M, et al. Rab11 is associated with transferrin-containing recycling compartments in K562 cells. Biochem Biophys Res Commun.,1997,239(2):612-616
[56]Casanova J E, Wang X, Kumar R, et al. Association of Rab25 and Rab11a with the apical recycling system of polarized Madin-Darby canine kidney cells. Mol Biol Cell,1999,10(1):47-61
[57]Bucci C, Thomsen P, Nicoziani P, et al. Rab7:a key to lysosome biogenesis. Mol Biol Cell,2000,11(2):467-480
[58]Meresse S, Gorvel J P, Chavrier P. The rab7 GTPase resides on a vesicular compartment connected to lysosomes. J Cell Sci.,1995,108 (Pt 11):3349-3358
[59]von Mollard G F, Nothwehr S F, Stevens T H. The yeast v-SNARE Vtilp mediates two vesicle transport pathways through interactions with the t-SNAREs Sed5p and Pep12p. J Cell Biol.,1997,137(7):1511-1524
[60]Holthuis J C, Nichols B J, Dhruvakumar S, et al. Two syntaxin homologues in the TGN/endosomal system of yeast. EMBO J.,1998,17(1):113-126
[61]Fasshauer D, Antonin W, Margittai M, et al. Mixed and non-cognate SNARE complexes. Characterization of assembly and biophysical properties. J Biol Chem., 1999,274(22):15440-15446
[62]Yang B, Gonzalez L J, Prekeris R, et al. SNARE interactions are not selective. Implications for membrane fusion specificity. J Biol Chem.,1999,274(9): 5649-5653
[63]Hickey C M, Wickner W. HOPS initiates vacuole docking by tethering membranes before trans-SNARE complex assembly. Mol Biol Cell,2010,21(13):2297-2305
[64]Sun Q, Westphal W, Wong K N, et al. Rubicon controls endosome maturation as a Rab7 effector. Proc Natl Acad Sci U S A,2010,107(45):19338-19343
[65]Antonin W, Holroyd C, Fasshauer D, et al. A SNARE complex mediating fusion of late endosomes defines conserved properties of SNARE structure and function. EMBO J.,2000,19(23):6453-6464
[66]Hay J C. SNARE complex structure and function. Exp Cell Res.2001,271(1): 10-21
[67]Sternberg P W. Working in the post-genomic C. elegans world. Cell,2001,105(2): 173-176
[68]Grant B, Hirsh D. Receptor-mediated endocytosis in the Caenorhabditis elegans oocyte. Mol Biol Cell,1999,10(12):4311-4326
[69]Grant B, Zhang Y, Paupard M C, et al. Evidence that RME-1, a conserved C. elegans EH-domain protein, functions in endocytic recycling. Nat Cell Biol.,2001, 3(6):573-579
[70]Zhang Y, Grant B, Hirsh D. RME-8, a conserved J-domain protein, is required for endocytosis in Caenorhabditis elegans. Mol Biol Cell,2001,12(7):2011-2021
[71]Treusch S, Knuth S, Slaugenhaupt S A, et al. Caenorhabditis elegans functional orthologue of human protein h-mucolipin-1 is required for lysosome biogenesis. Proc Natl Acad Sci U S A,2004,101(13):4483-4488
[72]Jones A K, Sattelle D B. Functional genomics of the nicotinic acetylcholine receptor gene family of the nematode, Caenorhabditis elegans. Bioessays,2004,26(1): 39-49
[73]Patton A, Knuth S, Schaheen B, et al. Endocytosis function of a ligand-gated ion channel homolog in Caenorhabditis elegans. Curr Biol.,2005,15(11):1045-1050
[74]Bagshaw R D, Callahan J W, Mahuran D J. The Arf-family protein, Ar18b, is involved in the spatial distribution of lysosomes. Biochem Biophys Res Commun., 2006,344(4):1186-1191
[75]Hofmann I, Munro S. An N-terminally acetylated Arf-like GTPase is localised to lysosomes and affects their motility. J Cell Sci.,2006,119(Pt 8):1494-1503
[76]Nakae I, Fujino T, Kobayashi T, et al. The arf-like GTPase Ar18 mediates delivery of endocytosed macromolecules to lysosomes in Caenorhabditis elegans. Mol Biol Cell,2010,21(14):2434-2442
[77]Fire A, Xu S, Montgomery M K, et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature,1998,391(6669):806-811
[78]Winston W M, Molodowitch C, Hunter C P. Systemic RNAi in C. elegans requires the putative transmembrane protein SID-1. Science,2002,295(5564):2456-2459
[79]Guo S, Kemphues K J. par-1, a gene required for establishing polarity in C. elegans embryos, encodes a putative Ser/Thr kinase that is asymmetrically distributed. Cell, 1995,81(4):611-620
[80]Maine E M. RNAi As a tool for understanding germline development in Caenorhabditis elegans:uses and cautions. Dev Biol.,2001,239(2):177-189
[81]Sharp P A, Zamore P D. Molecular biology. RNA interference. Science,2000, 287(5462):2431-2433
[82]Tchurikov N A, Chistyakova L G, Zavilgelsky G B, et al. Gene-specific silencing by expression of parallel complementary RNA in Escherichia coli. J Biol Chem., 2000,275(34):26523-26529
[83]Kamath R S, Martinez-Campos M, Zipperlen P, et al. Effectiveness of specific RNA-mediated interference through ingested double-stranded RNA in Caenorhabditis elegans. Genome Biol.,2001,2(1):H2
[84]Piatkevich K D, Verkhusha V V. Advances in engineering of fluorescent proteins and photoactivatable proteins with red emission. Curr Opin Chem Biol.,2010,14(1): 23-29
[85]Day R N, Davidson M W. The fluorescent protein palette:tools for cellular imaging. Chem Soc Rev.,2009,38(10):2887-2921
[86]Boulin T, Etchberger J F, Hobert O. Reporter gene fusions. WormBook,2006:1-23
[87]Teramoto T, Iwasaki K. Intestinal calcium waves coordinate a behavioral motor program in C. elegans. Cell Calcium.,2006,40(3):319-327
[88]酒亚明,张蓉颖,吴政星.线虫基因显微注射和整合技术——设备、操作与指南.生物化学与生物物理进展,2009,36(5)：648-652
[89]Tsuchiya M, Price S R, Tsai S C, et al. Molecular identification of ADP-ribosylation factor mRNAs and their expression in mammalian cells. J Biol Chem.,1991,266(5): 2772-2777
[90]Kumari S, Mayor S. ARF1 is directly involved in dynamin-independent endocytosis. Nat Cell Biol.,2008,10(1):30-41
[91]Kostich M, Fire A, Fambrough D M. Identification and molecular-genetic characterization of a LAMP/CD68-like protein from Caenorhabditis elegans. J Cell Sci.,2000,113 (Pt 14):2595-2606
[92]Jackson C L, Casanova J E. Turning on ARF:the Sec7 family of guanine-nucleotide-exchange factors. Trends Cell Biol.,2000,10(2):60-67
[93]Sato K, Sato M, Audhya A, et al. Dynamic regulation of caveolin-1 trafficking in the germ line and embryo of Caenorhabditis elegans. Mol Biol Cell,2006,17(7): 3085-3094
[94]Balklava Z, Pant S, Fares H, et al. Genome-wide analysis identifies a general requirement for polarity proteins in endocytic traffic. Nat Cell Biol.,2007,9(9): 1066-1073
[95]Greener T, Grant B, Zhang Y, et al. Caenorhabditis elegans auxilin:a J-domain protein essential for clathrin-mediated endocytosis in vivo. Nat Cell Biol.,2001, 3(2):215-219
[96]Nilsson L, Conradt B, Ruaud A F, et al. Caenorhabditis elegans num-1 negatively regulates endocytic recycling. Genetics,2008,179(1):375-387
[97]Fares H, Greenwald I. Genetic analysis of endocytosis in Caenorhabditis elegans: coelomocyte uptake defective mutants. Genetics,2001,159(1):133-145
[98]Brenner S. The genetics of Caenorhabditis elegans. Genetics.1974,77(1):71-94
[99]Lu Q, Zhang Y, Hu T, et al. C. elegans Rab GTPase 2 is required for the degradation of apoptotic cells. Development,2008,135(6):1069-1080
[100]Poteryaev D, Fares H, Bowerman B, et al. Caenorhabditis elegans SAND-1 is essential for RAB-7 function in endosomal traffic. EMBO J.,2007,26(2):301-312
[101]Bednarek E M, Schaheen L, Gaubatz J, et al. The plasma membrane calcium ATPase MCA-3 is required for clathrin-mediated endocytosis in scavenger cells of Caenorhabditis elegans. Traffic,2007,8(5):543-553
[102]Nicot A S, Fares H, Payrastre B, et al. The phosphoinositide kinase PIKfyve/Fablp regulates terminal lysosome maturation in Caenorhabditis elegans. Mol Biol Cell, 2006,17(7):3062-3074
[103]Li Y, Kelly W G, Logsdon J J, et al. Functional genomic analysis of the ADP-ribosylation factor family of GTPases:phylogeny among diverse eukaryotes and function in C. elegans. FASEB J.,2004,18(15):1834-1850
[104]Simmer F, Moorman C, van der Linden A M, et al. Genome-wide RNAi of C. elegans using the hypersensitive rrf-3 strain reveals novel gene functions. PLoS Biol.,2003,1(1):E12
[105]Lin S X, Grant B, Hirsh D, et al. Rme-1 regulates the distribution and function of the endocytic recycling compartment in mammalian cells. Nat Cell Biol.,2001,3(6): 567-572
[106]Hersh B M, Hartwieg E, Horvitz H R. The Caenorhabditis elegans mucolipin-like gene cup-5 is essential for viability and regulates lysosomes in multiple cell types. Proc Natl Acad Sci U S A,2002,99(7):4355-4360
[107]Piper R C, Luzio J P. CUPpling calcium to lysosomal biogenesis. Trends Cell Biol., 2004,14(9):471-473
[108]Vonderheit A, Helenius A. Rab7 associates with early endosomes to mediate sorting and transport of Semliki forest virus to late endosomes. PLoS Biol.,2005,3(7): e233
[109]Tischler J, Lehner B, Chen N, et al. Combinatorial RNA interference in Caenorhabditis elegans reveals that redundancy between gene duplicates can be maintained for more than 80 million years of evolution. Genome Biol.,2006,7(8): R69
[110]Gouda K, Matsunaga Y, Iwasaki T, et al. An altered method of feeding RNAi that knocks down multiple genes simultaneously in the nematode Caenorhabditis elegans. Biosci Biotechnol Biochem.,2010,74(11):2361-2365
[111]Luo L, Hannemann M, Koenig S, et al. The Caenorhabditis elegans GARP complex contains the conserved Vps51 subunit and is required to maintain lysosomal morphology. Mol Biol Cell,2011,22(14):2564-2578
[112]Gaidarov I, Keen J H. Phosphoinositide-AP-2 interactions required for targeting to plasma membrane clathrin-coated pits. J Cell Biol.,1999,146(4):755-764
[113]Ford M G, Pearse B M, Higgins M K, et al. Simultaneous binding of Ptdlns(4,5)P2 and clathrin by AP180 in the nucleation of clathrin lattices on membranes. Science, 2001,291(5506):1051-1055
[114]Sato K, Ernstrom G G, Watanabe S, et al. Differential requirements for clathrin in receptor-mediated endocytosis and maintenance of synaptic vesicle pools. Proc Natl Acad Sci U S A.2009,106(4):1139-1144
[115]陈大华,叶和春,李国凤等.绿色荧光蛋白基因在青蒿转基因芽中的表达.植物学报,1999,41(5)：490
[116]Norbury C C. Drinking a lot is good for dendritic cells. Immunology,2006,117(4): 443-451
[117]Foster F M, Traer C J, Abraham S M, et al. The phosphoinositide (PI) 3-kinase family. J Cell Sci.,2003,116(Pt 15):3037-3040
[118]Backer J M. The regulation and function of Class Ⅲ PI3Ks:novel roles for Vps34. Biochem J.,2008,410(1):1-17
[119]Vieira O V, Botelho R J, Rameh L, et al. Distinct roles of class Ⅰ and class Ⅲ phosphatidylinositol 3-kinases in phagosome formation and maturation. J Cell Biol., 2001,155(1):19-25
[120]Christoforidis S, Mcbride H M, Burgoyne R D, et al. The Rab5 effector EEA1 is a core component of endosome docking. Nature,1999,397(6720):621-625
[121]Stein M P, Feng Y, Cooper K L, et al. Human VPS34 and p150 are Rab7 interacting partners. Traffic,2003,4(11):754-771
[122]Chardin P, Paris S, Antonny B, et al. A human exchange factor for ARF contains Sec7-and pleckstrin-homology domains. Nature,1996,384(6608):481-484
[123]Robinson M S, Watts C, Zerial M. Membrane dynamics in endocytosis. Cell,1996, 84(1):13-21
[124]Gruenberg J, Maxfield F R. Membrane transport in the endocytic pathway. Curr Opin Cell Biol.,1995,7(4):552-563
[125]Pfeffer S R. Rab GTPases:master regulators of membrane trafficking. Curr Opin Cell Biol.,1994,6(4):522-526
[126]Lombardi D, Soldati T, Riederer M A, et al. Rab9 functions in transport between late endosomes and the trans Golgi network. EMBO J.,1993,12(2):677-682
[127]Laurent O, Bruckert F, Adessi C, et al. In vitro reconstituted Dictyostelium discoideum early endosome fusion is regulated by Rab7 but proceeds in the absence of ATP-Mg2+from the bulk solution. J Biol Chem.,1998,273(2):793-799
[128]Mills I G, Jones A T, Clague M J. Involvement of the endosomal autoantigen EEA1 in homotypic fusion of early endosomes. Curr Biol.,1998,8(15):881-884
[129]Mayer A, Wickner W, Haas A. Secl8p (NSF)-driven release of Secl7p (alpha-SNAP) can precede docking and fusion of yeast vacuoles. Cell,1996,85(1): 83-94
[130]Haas A, Scheglmann D, Lazar T, et al. The GTPase Ypt7p of Saccharomyces cerevisiae is required on both partner vacuoles for the homotypic fusion step of vacuole inheritance. EMBO J.,1995,14(21):5258-5270
[131]Tian Y, Li Z, Hu W, et al. C. elegans screen identifies autophagy genes specific to multicellular organisms. Cell,2010,141(6):1042-1055
[132]Duncan R, Pratten M K. Membrane economics in endocytic systems. J Theor Biol., 1977,66(4):727-735
[133]Toth M L, Simon P, Kovacs A L, et al. Influence of autophagy genes on ion-channel-dependent neuronal degeneration in Caenorhabditis elegans. J Cell Sci., 2007,120(Pt6):1134-1141
[134]Nonet M L. Visualization of synaptic specializations in live C. elegans with synaptic vesicle protein-GFP fusions. J Neurosci Methods,1999,89(1):33-40
[135]Sakamoto R, Byrd D T, Brown H M, et al. The Caenorhabditis elegans UNC-14 RUN domain protein binds to the kinesin-1 and UNC-16 complex and regulates synaptic vesicle localization. Mol Biol Cell,2005,16(2):483-496
[136]Sato M, Sato K, Fonarev P, et al. Caenorhabditis elegans RME-6 is a novel regulator of RAB-5 at the clathrin-coated pit. Nat Cell Biol.,2005,7(6):559-569
[137]Chen C C, Schweinsberg P J, Vashist S, et al. RAB-10 is required for endocytic recycling in the Caenorhabditis elegans intestine. Mol Biol Cell,2006,17(3): 1286-1297
[138]Clokey G V, Jacobson L A. The autofluorescent "lipofuscin granules" in the intestinal cells of Caenorhabditis elegans are secondary lysosomes. Mech Ageing Dev.,1986,35(1):79-94
[139]Hermann G J, Schroeder L K, Hieb C A, et al. Genetic analysis of lysosomal trafficking in Caenorhabditis elegans. Mol Biol Cell,2005,16(7):3273-3288
[140]Ashrafi K, Chang F Y, Watts J L, et al. Genome-wide RNAi analysis of Caenorhabditis elegans fat regulatory genes. Nature,2003,421(6920):268-272
[141]Hansen M, Chandra A, Mitic L L, et al. A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS Genet.,2008,4(2):e24
[142]Melendez A, Talloczy Z, Seaman M, et al. Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science,2003,301(5638): 1387-1391
[143]Spanier B, Sturzenbaum S R, Holden-Dye L M, et al. Caenorhabditis elegans neprilysin NEP-1:an effector of locomotion and pharyngeal pumping. J Mol Biol., 2005,352(2):429-437
[144]Chiang J T, Steciuk M, Shtonda B, et al. Evolution of pharyngeal behaviors and neuronal functions in free-living soil nematodes. J Exp Biol.,2006,209(Pt 10): 1859-1873
[145]Dal Santo P, Logan M A, Chisholm A D, et al. The inositol trisphosphate receptor regulates a 50-second behavioral rhythm in C. elegans. Cell,1999,98(6):757-767
[146]Mesce K A, Pierce-Shimomura J T. Shared Strategies for Behavioral Switching: Understanding How Locomotor Patterns are Turned on and Off. Front Behav Neurosci.,2010,4
[147]Pierce-Shimomura J T, Chen B L, Mun J J, et al. Genetic analysis of crawling and swimming locomotory patterns in C. elegans. Proc Natl Acad Sci U S A,2008, 105(52):20982-20987
[148]Berri S, Boyle J H, Tassieri M, et al. Forward locomotion of the nematode C. elegans is achieved through modulation of a single gait. HFSP J.,2009,3(3): 186-193
[149]Boyle J H, Berri S, Tassieri M, et al. Gait Modulation in C. elegans:It's Not a Choice, It's a Reflex!. Front Behav Neurosci.,2011,5:10
[150]Vidal-Gadea A, Topper S, Young L, et al. Caenorhabditis elegans selects distinct crawling and swimming gaits via dopamine and serotonin. Proc Natl Acad Sci U S A,2011,108(42):17504-17509
[151]Zhao H, Nonet M L. A retrograde signal is involved in activity-dependent remodeling at a C. elegans neuromuscular junction. Development,2000,127(6): 1253-1266
[152]Mcewen J M, Madison J M, Dybbs M, et al. Antagonistic regulation of synaptic vesicle priming by Tomosyn and UNC-13. Neuron.,2006,51(3):303-315
[153]Goodman M B, Hall D H, Avery L, et al. Active currents regulate sensitivity and dynamic range in C. elegans neurons. Neuron.,1998,20(4):763-772
[154]Kerr R, Lev-Ram V, Baird G, et al. Optical imaging of calcium transients in neurons and pharyngeal muscle of C. elegans. Neuron.,2000,26(3):583-594
[155]Clark D A, Biron D, Sengupta P, et al. The AFD sensory neurons encode multiple functions underlying thermotactic behavior in Caenorhabditis elegans. J Neurosci., 2006,26(28):7444-7451
[156]Zeng F, Rohde C B, Yanik M F. Sub-cellular precision on-chip small-animal immobilization, multi-photon imaging and femtosecond-laser manipulation. Lab Chip,2008,8(5):653-656
[157]Lewis J A, Wu C H, Berg H, et al. The genetics of levamisole resistance in the nematode Caenorhabditis elegans. Genetics,1980,95(4):905-928
[158]Mccarter J, Bartlett B, Dang T, et al. On the control of oocyte meiotic maturation and ovulation in Caenorhabditis elegans. Dev Biol.,1999,205(1):111-128
[159]Wu Z, Ghosh-Roy A, Yanik M F, et al. Caenorhabditis elegans neuronal regeneration is influenced by life stage, ephrin signaling, and synaptic branching. Proc Natl Acad Sci U S A,2007,104(38):15132-15137
[160]Norris A D, Dyer J O, Lundquist E A. The Arp2/3 complex, UNC-115/abLIM, and UNC-34/Enabled regulate axon guidance and growth cone filopodia formation in Caenorhabditis elegans. Neural Dev.,2009,4:38
[161]Ghosh R, Emmons S W. Episodic swimming behavior in the nematode C. elegans. J Exp Biol.,2008,211(Pt 23):3703-3711
[162]Richmond J E, Jorgensen E M. One GABA and two acetylcholine receptors function at the C. elegans neuromuscular junction. Nat Neurosci.,1999,2(9): 791-797
[163]Chung K, Crane M M, Lu H. Automated on-chip rapid microscopy, phenotyping and sorting of C. elegans. Nat Methods,2008,5(7):637-643
[164]Chokshi T V, Ben-Yakar A, Chronis N. CO2 and compressive immobilization of C. elegans on-chip. Lab Chip,2009,9(1):151-157
[165]Rohde C B, Zeng F, Gonzalez-Rubio R, et al. Microfluidic system for on-chip high-throughput whole-animal sorting and screening at subcellular resolution. Proc Natl Acad Sci U S A,2007,104(35):13891-13895
[166]Allen P B, Sgro A E, Chao D L, et al. Single-synapse ablation and long-term imaging in live C. elegans. J Neurosci Methods,2008,173(1):20-26
[167]Hulme S E, Shevkoplyas S S, Apfeld J, et al. A microfabricated array of clamps for immobilizing and imaging C. elegans. Lab Chip,2007,7(11):1515-1523
[168]Hulme S E, Shevkoplyas S S, Mcguigan A P, et al. Lifespan-on-a-chip:microfluidic chambers for performing lifelong observation of C. elegans. Lab Chip,2010,10(5): 589-597
[169]Mcdonald J C, Duffy D C, Anderson J R, et al. Fabrication of microfluidic systems in poly(dimethylsiloxane). Electrophoresis,2000,21(1):27-40
[170]Duffy D C, Mcdonald J C, Schueller O J, et al. Rapid Prototyping of Microfluidic Systems in Poly(dimethylsiloxane). Anal Chem.,1998,70(23):4974-4984
[171]Henderson S T, Johnson T E. daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans. Curr Biol.,2001, 11(24):1975-1980
[172]Lin K, Hsin H, Libina N, et al. Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling. Nat Genet.,2001,28(2): 139-145
[173]Ogg S, Paradis S, Gottlieb S, et al. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature,1997, 389(6654):994-999
[174]Johnson T E, Mitchell D H, Kline S, et al. Arresting development arrests aging in the nematode Caenorhabditis elegans. Mech Ageing Dev.,1984,28(1):23-40
[175]Paradis S, Ailion M, Toker A, et al. A PDK1 homolog is necessary and sufficient to transduce AGE-1 PI3 kinase signals that regulate diapause in Caenorhabditis elegans. Genes Dev.,1999,13(11):1438-1452
[176]Lin K, Dorman J B, Rodan A, et al. daf-16:An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Science,1997, 278(5341):1319-1322
[177]Murakami S, Johnson T E. A genetic pathway conferring life extension and resistance to UV stress in Caenorhabditis elegans. Genetics,1996,143(3): 1207-1218