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研究生:翁浩賢
研究生(外文):ONG, HO-YIN
論文名稱:利用果蠅研究氯離子通道-c的功能與作用機制
論文名稱(外文):Study of the function and mechanism of Chloride channels-c (ClC-c) in Drosophila
指導教授:蔡玉真蔡玉真引用關係
指導教授(外文):TSAI, YU-CHEN
口試委員:陳仁祥孫以瀚陳俊宏姚季光
口試委員(外文):CHEN, REN-SHIANGSUN, Y. HENRYCHEN, CHUN-HONGYAO, CHI-KUANG
口試日期:2023-09-26
學位類別:碩士
校院名稱:東海大學
系所名稱:生命科學系
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2023
畢業學年度:112
語文別:中文
論文頁數:109
中文關鍵詞:氯離子通道-c人類ClC-3果蠅神經發育
外文關鍵詞:Chloride channels-chuman ClC-3 variantsDrosophilaneuronsdevelopment
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Chloride channels(ClC氯離子通道)會透過協助氯離子(Cl-)及質子進入胞內體膜內,以維持膜內的酸性。在人類中有九種氯離子通道,其中ClC-3蛋白主要位在胞內體膜和溶體膜以主動運輸的方式協助運送氯離子。目前在人類病患中發現八種位於ClC-3基因的突變,這些病患皆有發育遲緩、神經退化、大腦結構異常、行動能力下降以及視覺障礙。有研究發現小鼠缺失ClC-3會導致海馬迴的缺失,其中缺失ClC-3跟臨床上觀察到和ClC-3有關的腦白質退化症與腎小管病變等症狀吻合,但在ClC-3蛋白導致發育和神經異常相關的機制仍然未知。在本研究中利用果蠅作為模式生物,因為在果蠅上有許多實驗方法可以用作研究ClC的功能和表達。此外許多基因和訊息傳遞鏈在果蠅和人類上具高度保留性。果蠅上有3個氯離子通道基因,其中ClC-c和哺乳類ClC-3在演化上最接近,彼此有57%的蛋白質序列一致性。利用crispr/cas9技術構築的ClC-c突變果蠅會有生長遲緩並無法活到蛹期。在本研究中,利用果蠅作為模式生物去研究ClC-c的功能以及人類ClC-3病患基因變異背後的機制。利用內生性表達ClC-c-GFP轉殖基因的果蠅,發現ClC-c在果蠅胚胎、幼蟲和成蟲時期各個細胞均有表達。此外,利用ClC-c RNAi下調ClC-c或過度表達ClC-c,發現在果蠅幼蟲眼碟抑制ClC-c表達會導致視神經發育異常的現象,在幼蟲翅膀碟抑制ClC-c會導致成蟲翅膀發育異常,在果蠅成蟲時期全身性、神經或神經膠細胞中下調ClC-c,發現果蠅成蟲行動能力下降,顯示ClC-c可能在眼睛、翅膀發育和活動力上扮演重要的角色。接著透過人類的ClC-3和果蠅的ClC-c序列比對,發現人類ClC-3突變病人的8種突變點中,有6個位點在果蠅上具有保留性。因此可以利用轉殖果蠅研究這6個突變位置的功能。了解它們如何影響個體的生長與神經的發育。目前已建立6個ClC-c*點突變的轉殖果蠅株,在幼蟲的唾腺細胞分別表達6種ClC-c*,它們都分布在細胞的初級、次級和循環胞內體,並和內生性的ClC-c蛋白的位置相同。6種ClC-c*突變不會改變ClC-c蛋白在細胞內分布的位置。在幼蟲眼碟表達6種ClC-c*會導致視神經發育異常,但6種ClC-c*的眼碟沒有偵測到細胞凋亡的發生。在幼蟲翅碟表達4種ClC-c*會導致成蟲翅膀異常。在果蠅成蟲期全身性、神經或神經膠細胞中表達5種ClC-c*,發現果蠅成蟲行動能力下降,以上的發育異常和表達ClC-c RNAi的結果相似。由本實驗室初步的研究發現,在ClC-c突變的果蠅翅膀碟的翅囊中觀察到Jak/STAT的活性上升,利用Grh-STAT-lacZ的果蠅標記Jak/STAT訊息的活性,發現6種ClC-c*不會在翅膀碟翅囊影響Jak/STAT訊息的活性。先前中研院姚季光老師和我們實驗室發現ClC-c缺失的果蠅會有嚴重的發育遲緩和蛹期致死性,因此可以利用補償實驗在ClC-c缺失的果蠅中,表達人類的ClC-3,觀察此果蠅幼蟲生長遲緩和神經發育缺失是否恢復正常,以探討ClC-3是否和ClC-c具有相同功能。在缺失ClC-c的果蠅中,全身性的表達人類的 ClC-3可以拯救部份缺失ClC-c發育遲緩,並加快了成蛹的時間,但沒有拯救蛹期致死性。綜合以上結果,果蠅ClC-c會影響發育和神經,且透過神經影響活動能力。透過本研究進一步了解ClC-c的功能,及在果蠅的發育與神經上的影響。並希望透過果蠅的研究可以了解人類ClC-3突變病人的點突變致病的分子機制,為日後治療氯離子通道相關疾病上提供一個新研究的方向。
Chloride channels (ClC) are Cl- transporters and play an important role to maintain the acidity inside endocytic vesicles. There are nine chloride channels in humans. ClC-3 is an active Cl- transporter and expressed in endosomal and lysosomal membranes. Patients with ClC-3 mutants show developmental delay, brain abnormalities, mobility abnormalities and vision defects. Previous studies showed ClC-3 knockout mice result in hippocampus loss and showed similar clinical phenotype to ClC related symptoms like Leukodystrophy. The molecular mechanism of ClC-3 and its endogenous roles in development are still unknown. Drosophila is a good genetic system to study the function of human disease-related genes. Fly has many genetic tools. Most important genes and signaling pathways are evolutional conserved in fly and human. Fly contains three ClC proteins. ClC-c is closely related to mammalian ClC-3 and they share 57% identities in protein sequence. The ClC-c mutant was generated by the Crispr/Cas 9 technique and it showed developmental delay and lethality before pupal stages. In this study, I used Drosophila as a model to study ClC-c function and the effects of ClC-3 variants in human patients in vivo. First, the fly genomic ClC-c-GFP transgene was used to detect the ClC-c expression pattern during development. The results showed that ClC-c is ubiquitously expressed during development. Next, targeted expression of ClC-c RNAi by the GAL4/UAS system in developing eye led to defect in photoreceptor neurons. Expression of ClC-c RNAi in wing disc led to developmental defect in adult wing. Expression of ClC-c RNAi or ClC-c ubiquitously or in glial cells shows low mobility in the climbing assay. And these results showed ClC-c may play a role in developing eye and wing. Tissue specific expression of ClC-c RNAi in neuron cells showed mobility decline by the climbing assay. Mutation site of six ClC-3 variants in human patients are evolutional conserved with ClC-c in Drosophila. I cloned these six ClC-c*(* variants), generated transgenic flies and then analyzed their function in neurons and developmental processes in Drosophila. To study whether ClC-c* proteins change their subcellular location to affect the function of ClC-c, the results showed subcellular location of ClC-c* proteins is not changed in ClC-c* expression cells. Expression of six ClC-c* or ClC-c RNAi in developing eyes led to defect in photoreceptor neurons but no apoptotic signal is detected in the eye discs. On the other hand, expression of four ClC-c* mutants in developing wing induced adult wing defect. Expression of five ClC-c* mutants ubiquitously, in neurons cells or in glial cells showed low mobility in the climbing assays. In the previous studies from our laboratory, we found the Jak/STAT signaling is upregulated in wing pouch of ClC-c mutants. But the Jak/STAT signaling is not induced in wing pouch when ClC-c*mutants were expressed. In previous study from Yao’s lab in Academia Sinica and our laboratory, we found ClC-c mutants showed development delay and pupa lethality. To study whether human ClC-3 shares similiar function to fly ClC-c. I expressed human ClC-3 to rescue ClC-c mutant phenotype. Ubiquitously expression of ClC-3 in ClC-c mutants partial rescued development delay, but pupa lethality is not rescued in the ClC-c mutants. Based on the results, fly ClC-c regulated eye, wing development and adult mobility. Through my study, we can understand the molecular mechanism of ClC-3 variants in human patients and these may provide a new insight for therapeutic strategies for chloride channel-related diseases in the future.
目錄
目錄 3
圖表目錄 5
摘要 7
Abstract 9
前言 11
胞內體(endosome)和內吞作用(endocytosis) 11
氯離子通道(Chloride channels,ClC) 11
哺乳動物的ClC-3氯離子通道 12
人類ClC氯離子通道 13
人類的ClC-3氯離子通道 13
ClC-3點突變影響人類發育及神經 14
利用果蠅研究氯離子通道(ClC) 15
問題及假設 17
實驗材料 18
果蠅株 18
引子 20
免疫組織染色抗體 21
實驗方法 22
一、 聚合酶連鎖反應(PCR) 22
二、 iPoof聚合酶連鎖反應(PCR) 22
三、 定點突變聚合酶連鎖反應 22
四、 接合作用 23
五、 轉型作用-電穿孔法 23
六、 小量質體製備 24
七、 限制酶切割 24
八、 中量質體置備(QIAGEN) 24
九、 免疫螢光染色法 25
十、 果凍盤餵食實驗(Juice plate) 25
十一、 建立轉殖果蠅 26
十二、 爬行能力分析 26
實驗結果 28
人類ClC-3和果蠅ClC-c蛋白質的同源性 28
果蠅 ClC-c表達的位點和時期 28
研究果蠅ClC-c的功能 29
建立表達ClC-3*的轉殖果蠅(transgenic fly) 35
ClC-c*-GFP蛋白在細胞內表達的位置 36
研究ClC-3*突變的功能 38
ClC-3*的影響的分子機制 42
研究人類ClC-3-2和果蠅ClC-c-RC的是否具有相同功能 43
討論 43
在果蠅發育時期ClC-c全身性表達在細胞的胞內體上 44
ClC-c對果蠅發育的影響 44
ClC-3*點突變表達在各種胞內體之中 46
果蠅ClC-c*點突變對發育的影響 46
果蠅的ClC-c*對翅膀的功能 47
果蠅的ClC-c*對行動能力的功能 47
果蠅的ClC-c*影響發育的機制 48
人類ClC-3和果蠅ClC-c的功能 49
參考文獻 50


圖表目錄
圖表
圖 1 人類ClC-3-1和果蠅ClC-c RC蛋白質序列比較 58
圖 2 ClC-c在果蠅胚胎、幼蟲和成蟲會全面表達 59
圖 3 ClC-c在果蠅細胞初級、次級、循環胞內體中共同表達 60
圖 4 本實驗使用的Gal4 和與ClC-c 相關的UAS 果蠅株 61
圖 5 神經細胞失去ClC-c功能會造成幼蟲神經發育缺失 63
圖 6 利用elav-Gal4大量表達或失去ClC-c功能會造成幼蟲眼碟神經發育缺失 65
圖 7 利用GMR-Gal4大量表達或失去ClC-c功能會造成幼蟲眼碟神經發育缺失 67
圖 8 利用GMR-Gal4在眼碟視神經大量表達ClC-c或ClC-c RNAi會造成成蟲神經發育缺失 68
圖 9翅碟細胞失去ClC-c功能會造成幼蟲翅碟過度發育 69
圖 10 利用MS1096-Gal4在翅碟大量表達ClC-c或ClC-c RNAi會造成翅碟過度增生 71
圖 11 在果蠅翅膀上表達ClC-c RNAi 會影響成蟲時期翅膀的發育 72
圖 12 利用MS1096-Gal4在翅碟大量表達ClC-c或ClC-c RNAi會影響成蟲翅碟的發育 74
圖 13 在果蠅成蟲時期全身性、神經或神經膠上改變ClC-c 劑量會影響的行動能力 76
圖 14 人類ClC-3 與果蠅ClC-c序列比對 78
圖 15 果蠅ClC-c*-GFP轉殖基因 80
圖 16 構築UAS-ClC-c*-GFP的轉殖基因 82
圖 17 利用elav-Gal4表達ClC-c*-GFP會造成幼蟲眼碟神經發育缺失 84
圖 18 果蠅 ClC-c 表達在初級胞內體、次級胞內體和循環胞內體 86
圖 19 利用GMR-Gal4表達ClC-c*-GFP會造成幼蟲眼碟神經發育缺失 88
圖 20 利用GMR-Gal4在眼碟視神經表達ClC-c*-GFP會造成成蟲神經發育缺失 89
圖 21 利用MS1096-Gal4在翅碟表達ClC-c*-GFP會造成翅碟過度發育 91
圖 22 利用MS1096-Gal4在翅碟表達ClC-c*-GFP會影響成蟲翅碟的發育 93
圖 23 在果蠅成蟲時期全身性、神經或神經膠上表達ClC-c*會影響的行動能力 95
圖 24 表達ClC-c*-GFP在神經細胞中沒有偵測到細胞凋亡 97
圖 25 表達ClC-c*-GFP在翅碟中沒有影響JAK/STAT信號通路 99
圖 26 人類ClC-3部份拯救缺失ClC-c的發育遲緩加快了成蛹的時間,沒有拯救蛹期致死性。 100
附圖
附圖 1 人類ClC-3-1和ClC-c-PC的ClC/CBS蛋白質結構域序列比較 101
附圖 2 人類ClC-3剪接異構體1、ClC-3剪接異構體2和ClC-3剪接異構體4蛋白質序列比較 102
附圖 3 ClC-c 位於初級、次級和循環胞內體中 103
附圖 4 ClC-3的點突變和缺失突變導致發育遲緩以及智力障礙等症狀 105
附圖 5 ClC-3點突變的ClC-c在ClC-c蛋白的三度空間位置 107
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Scott, C.C., Vacca, F., and Gruenberg, J. (2014). Endosome maturation, transport and functions. Semin Cell Dev Biol 31, 2-10.
Settembre, C., Fraldi, A., Medina, D.L., and Ballabio, A. (2013). Signals from the lysosome: a control centre for cellular clearance and energy metabolism. Nat Rev Mol Cell Biol 14, 283-296.
Steinmeyer, K., Lorenz, C., Pusch, M., Koch, M.C., and Jentsch, T.J. (1994). Multimeric structure of ClC-1 chloride channel revealed by mutations in dominant myotonia congenita (Thomsen). EMBO J 13, 737-743.
Stobrawa, S.M., Breiderhoff, T., Takamori, S., Engel, D., Schweizer, M., Zdebik, A.A., Bosl, M.R., Ruether, K., Jahn, H., Draguhn, A., et al. (2001). Disruption of ClC-3, a chloride channel expressed on synaptic vesicles, leads to a loss of the hippocampus. Neuron 29, 185-196.
Thiemann, A., Grunder, S., Pusch, M., and Jentsch, T.J. (1992). A chloride channel widely expressed in epithelial and non-epithelial cells. Nature 356, 57-60.
Tsai, Y.C., Yao, J.G., Chen, P.H., Posakony, J.W., Barolo, S., Kim, J., and Sun, Y.H. (2007). Upd/Jak/STAT signaling represses wg transcription to allow initiation of morphogenetic furrow in Drosophila eye development. Dev Biol 306, 760-771.
Uchida, S., Sasaki, S., Furukawa, T., Hiraoka, M., Imai, T., Hirata, Y., and Marumo, F. (1993). Molecular cloning of a chloride channel that is regulated by dehydration and expressed predominantly in kidney medulla. J Biol Chem 268, 3821-3824.
Vanden Abeele, F., Skryma, R., Shuba, Y., Van Coppenolle, F., Slomianny, C., Roudbaraki, M., Mauroy, B., Wuytack, F., and Prevarskaya, N. (2002). Bcl-2-dependent modulation of Ca(2+) homeostasis and store-operated channels in prostate cancer cells. Cancer Cell 1, 169-179.
Yamada, K., Fuji, K., Shimada, T., Nishimura, M., and Hara-Nishimura, I. (2005). Endosomal proteases facilitate the fusion of endosomes with vacuoles at the final step of the endocytotic pathway. Plant J 41, 888-898.
Zhang, H.N., Zhou, J.G., Qiu, Q.Y., Ren, J.L., and Guan, Y.Y. (2006). ClC-3 chloride channel prevents apoptosis induced by thapsigargin in PC12 cells. Apoptosis 11, 327-336.
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