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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 王致恬(Chih-Tien Wang) | |
dc.contributor.author | Yu-Hung Tsai | en |
dc.contributor.author | 蔡毓紘 | zh_TW |
dc.date.accessioned | 2021-05-19T17:52:14Z | - |
dc.date.available | 2022-08-08 | |
dc.date.available | 2021-05-19T17:52:14Z | - |
dc.date.copyright | 2017-08-08 | |
dc.date.issued | 2017 | |
dc.date.submitted | 2017-07-31 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/7749 | - |
dc.description.abstract | Sytnaptotagmins (Syts) 的功能是扮演一個鈣離子感受器,進而去調控神經及神經內分泌細胞中胞吐作用的動態變化。Syts 至少有17種亞型已在哺乳動物中被發現,並且不同亞型的C2A及C2B擁有不同跟鈣離子結合的親和力。我們先前已發現Syt III (一種擁有6個鈣離子結合位的亞型)會在大鼠出生後4-6天(視覺網絡發育的關鍵時期),突然在視網膜神經節細胞大量表現,由此可知Syt III在發育中的神經系統中可能扮演一個調控神經突觸活性的角色。此外,我們先前過量表現Syt III在PC12細胞中,結果緻密核心囊泡釋放的頻率和控制組與突變組(Syt III-C2AB*, 一種降低跟鈣離子結合的能力的突變)相比明顯地增加。然而,Syt III如何調控囊泡釋放的詳細分子機制目前還不清楚。在本論文中,我們過量表現Syt III或Syt III-C2AB*在PC12細胞中,於過量表現後第三天,利用免疫染色及內源性免疫沉澱來進行研究。結果發現Syt III僅和緻密核心囊泡部分重疊,但在被KCl刺激去極化後,Syt III卻與細胞膜高度重疊。另外,Syt III會和SNAP-25或Syntaxin (t-SNAREs,位在細胞膜上的蛋白質)交互作用,此結果與免疫染色一致,並且,阻斷跟鈣離子結合能力(Syt III-C2AB*)會降低Syt III跟t-SNAREs交互作用的量。我們還發現了被KCl刺激後,過量表現Syt III會降低跟溶酶體重疊;相反地,和外泌體重疊的比例卻增加。並且,在KCl刺激下,外泌體的釋放受到鈣離子跟C2AB結合來調控。然而,以上的結果並未在發育中大鼠視網膜被初步發現。這些結果顯示了在PC12細胞中,Syt III會透過跟SNAP-25或Syntaxin交互作用,進而調控囊泡融合孔的動態變化。除此之外,Syt III還有可能透過鈣離子跟C2AB結合而調控溶酶體及外泌體的釋放。 | zh_TW |
dc.description.abstract | Synaptotagmins (Syts) function as Ca2+ sensors that regulate the kinetics of exocytosis in neurons and neuroendocrine cells. At least 17 Syt isoforms have been found in mammals and possess variable calcium-binding affinities in C2 domains (C2A and C2B). Our previous studies found that Syt III (a particular isoform with six calcium-binding sites) is significantly up-regulated in P4-P6 (a critical period of visual circuit development) rat retinal ganglion cells, suggesting that Syt III may play a unique role in regulating synaptic activity in the developing nervous system. In addition, overexpressing Syt III in PC12 cells increases the frequency of DCV release after KCl depolarization compared to control or Syt III-C2AB* (a mutant harboring the abolished calcium-binding sites). However, the molecular mechanism underlying Syt III’s regulation of vesicle release remains elusive. In this study, we overexpressed Syt III or Syt III-C2AB* in PC12 cells. At 72 hr post transfection, we performed immunoflurorescence staining and endogenous co-immunoprecipitation. We found that Syt III was poorly colocalized with dense-core vesicles (DCVs) but highly colocalized to plasma membrane after KCl depolarization. Moreover, abolishing the calcium-binding sites in Syt III decreased its interaction with SNAP-25 or Syntaxin (two t-SNAREs), consistent with the localization of Syt III to plasma membrane. We also found that Syt III down-regulated the localization to lysosome upon KCl depolarization. By contrast, overexpressing Syt III enhanced the colocalization ratios of Syt III overlapping with exosomes. Furthermore, exosome export was regulated by Ca2+-binding to the C2AB domains of Syt III upon KCl depolarization. Nevertheless, these effects were not shown in developing rat retinas. These results suggested that Syt III regulates the kinetics of fusion pores by interacting with SNAP-25 or Syntaxin, and this interaction acts through calcium binding to its C2AB domains. In addition, Syt III may also modulate the release of lysosomes or exosomes by Ca2+-binding to the C2AB domains. | en |
dc.description.provenance | Made available in DSpace on 2021-05-19T17:52:14Z (GMT). No. of bitstreams: 1 ntu-106-R04b43001-1.pdf: 10893785 bytes, checksum: 1c0ae8cd389895af5e93ffbf607014a7 (MD5) Previous issue date: 2017 | en |
dc.description.tableofcontents | 口試委員審定書……………………………………………………………………….
致謝 II 中文摘要 IV Abstract VI Abbreviations VIII Contents X Chapter I 1 Introduction 1 1.1 Calcium-dependent exocytosis 1 1.2 Fusion pores 2 1.3 Molecular mechanisms of membrane fusion 3 1.4 The synaptotagmin family 4 1.5 Synaptotagmin I (Syt I) 5 1.6 Synaptotagmin III (Syt III) 6 1.7 Up-regulation of Syt III expression during the critical period of visual circuit development 7 1.8 Exosomes 8 1.9 The role and working hypothesis of Syt III in different organelles 8 1.10 Specific aims and experimental design 10 Chapter II 13 Materials and Methods 13 2.1 Plasmid information 13 2.2 Competent cells 13 2.3 Cell culture 14 2.4 Transient transfection 15 2.5 Immunofluorescence staining 15 2.6 Coimmunoprecipitation and immunoblotting analysis 17 2.7 Exosome isolation 19 2.8 Animals 20 2.9 Dissection of retinas 20 2.10 Statistics 21 Chapter III 22 Results 22 3.1 The localization of Syt III 22 3.2 The mechanism of Syt III and its C2AB mutant in regulating Ca2+-dependent exocytosis 24 3.3 Syt III-C2AB* tends to localize to lysosomes compared to Syt III 28 3.4 Syt III may regulate exosome export by Ca2+ binding to the C2AB domains after KCl depolarization 29 3.5 The mechanism of Syt III and its C2AB mutant in regulating Ca2+-dependent exocytosis in developing rat retinas 32 3.6 The isolated pellets from the supernatant in developing rat retinas. 35 Chapter IV 36 Discussion 36 4.1 The interaction between Syt III and SNAREs 37 4.2 The effects of Syt III interacting with SNAREs 38 4.3 The regulation of the export of exosomes 38 4.4 The function of exosomes in the nervous system 40 References 42 Figures for Introduction 47 Figure 1. The process of Ca2+-dependent exocytosis. 48 Figure 2. Full-fusion events and kiss-and-run events in calcium-dependent exocytosis. 49 Figure 3. Membrane fusion machinery. 50 Figure 4. The structure of synaptotagmin. 51 Figure 5. Diagram of the structure of C2 domains in Synaptotagmin III. 52 Figure 6. The mRNA and protein expression levels of Syt III in developing rat retinal neurons. 54 Figure 7. The protein expression level of SNAREs after transfection. 55 Figures for Results 56 Figure 8. Subcellular localization of Syt III and HA in transfected PC12 cells. 58 Figure 9. Subcellular localization of Syt III and Chromogranin B (ChB) in transfected PC12 cells after treatment of normal buffer. 61 Figure 10. Subcellular localization of Syt III and Chromogranin B (ChB) in transfected PC12 cells after KCl depolarization. 64 Figure 11. Representative images and quantitative subcellular localization of Syt III and Chromogranin B (ChB) in transfected PC12 cells. 66 Figure 12. Subcellular localization of Syt III and SNAP-25 (SN25) in transfected PC12 cells after treatment of normal buffer. 69 Figure 13. Subcellular localization of Syt III and SNAP-25 (SN25) in transfected PC12 cells after KCl depolarization. 71 Figure 14. Representative images and quantitative subcellular localization of Syt III and SNAP-25 (SN25) in transfected PC12 cells. 73 Figure 15. The major band of HA-Syt III in PC12 cells. 77 Figure 16. The protein expression level of SNAREs in transfected cells in the presence or absence of KCl treatment. 78 Figure 17. The endogenous interaction between Syt III and SNAP-25 (SN25) requires calcium binding to the C2AB domains of Syt III in the absence of KCl treatment. 80 Figure 18. The endogenous interaction between Syt III and SNAP-25 (SN25) requires calcium binding to the C2AB domains of Syt III in the presence of KCl treatment. 82 Figure 19. The endogenous interaction between Syt III and SNARE proteins in the absence or presence of KCl treatment. 85 Figure 20. Subcellular localization of Syt III and Lamp1 in transfected PC12 cells after treatment of normal buffer. 88 Figure 21. Subcellular localization of Syt III and Lamp1 in transfected PC12 cells after KCl depolarization. 91 Figure 22. Representative images and quantitative subcellular localization of Syt III and Lamp1 in transfected PC12 cells. 93 Figure 23. Subcellular localization of HA and CD63 in transfected PC12 cells after treatment of normal buffer. 96 Figure 24. Subcellular localization of HA and CD63 in transfected PC12 cells after KCl depolarization. 99 Figure 25. Representative images and quantitative subcellular localization of HA and CD63 in transfected PC12 cells. 101 Figure 26. Subcellular localization of HA and CD9 in transfected PC12 cells after treatment of normal buffer. 104 Figure 27. Subcellular localization of HA and CD9 in transfected PC12 cells after KCl depolarization. 107 Figure 28. Representative images and quantitative subcellular localization of HA and CD9 in transfected PC12 cells. 109 Figure 29. The protocol to purify exosomes from the supernatant of PC12 cells upon KCl depolarization. 110 Figure 30. Isolated exosomes from PC12 supernatant contain the exosome markers (CD9 and CD63). 112 Figure 31. The procedures for collecting whole retinas and purified exosomes in developing rat retinas in the presence or absence of KCl deporlarization. 114 Figure 32. The protein expression levels of Syt III and SNAREs in developing rat retinas in the presence or absence of KCl depolarization. 117 Figure 33. The protein expression levels of Syt III and SNAREs in developing rat retinas. 119 Figure 34. The endogenous interactions between Syt III and SNARE proteins in developing rat retinas. 121 Figure 35. Isolated pellets from developing rat retinas do not contain any exosome marker (CD9 and CD63). 122 Figure 36. The role of Syt III in regulating trafficking of different organelles. 123 Appendix 124 Appendix 1. The endogenous interaction between Syt III and SNARE proteins in the absence or presence of KCl treatment. 126 Appendix 2. The endogenous interaction between SNAP-25 (SN25) and Syt III in the absence or presence of KCl treatment. 128 Appendix 3. Isolated exosomes from the PC12 cell supernatant contain the exosome markers (CD9 and CD63). 130 Appendix 4. 2016 Annual meeting of the Society for Neuroscience (San Diego, U.S.A. 11/12-16/2016): Abstract and poster....................................................................131 Appendix 5. The 2017 Poster Competition in the Institute of Molecular and Cellular Biology at National Taiwan University, Taipei, Taiwan (5/26 2017): Abstract and Poster…………………………………………………………………………....133 | |
dc.language.iso | en | |
dc.title | 第三型突觸連結蛋白在PC12細胞與發育視網膜神經元中
調控胞吐作用的機制 | zh_TW |
dc.title | Cellular and Molecular Mechanisms of Synaptotagmin III-Regulated Exocytosis in PC12 Cells and Developing Retinal Neurons | en |
dc.type | Thesis | |
dc.date.schoolyear | 105-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 盧主欽(Juu-Chin Lu),徐立中,周申如,胡孟君 | |
dc.subject.keyword | 第三型突觸連結蛋白,緻密核心囊泡,SNAP-25,溶?體,外泌體, | zh_TW |
dc.subject.keyword | Synaptotagmin III,dense-core vesicle,SNAP-25,lysosome,exosome, | en |
dc.relation.page | 134 | |
dc.identifier.doi | 10.6342/NTU201702315 | |
dc.rights.note | 同意授權(全球公開) | |
dc.date.accepted | 2017-07-31 | |
dc.contributor.author-college | 生命科學院 | zh_TW |
dc.contributor.author-dept | 分子與細胞生物學研究所 | zh_TW |
顯示於系所單位: | 分子與細胞生物學研究所 |
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