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系統識別號 U0002-1901201117302600
中文論文名稱 斑馬魚酪胺酸磷酸水解酶 (ptp4a1 & ptp4a2) 在胚胎早期的功能分析
英文論文名稱 Functional analysis of zebrafish ptp4a1 & ptp4a2 during early embryonic development
校院名稱 淡江大學
系所名稱(中) 化學學系碩士班
系所名稱(英) Department of Chemistry
學年度 99
學期 1
出版年 100
研究生中文姓名 李訓慈
研究生英文姓名 Hsun-Tzu Lee
學號 697161031
學位類別 碩士
語文別 中文
口試日期 2011-01-10
論文頁數 89頁
口試委員 指導教授-陳曜鴻
委員-林明德
委員-蔡振寧
委員-王芸馨
委員-周三芳
中文關鍵字 斑馬魚  ptp4a1  ptp4a2 
英文關鍵字 zebrafish  ptp4a1  ptp4a2 
學科別分類 學科別自然科學化學
中文摘要 第四類酪胺酸磷酸水解酶 (protein tyrosine phosphatase 4A, ptp4a) 可影響細胞的生長、分裂、移動及分化,且多表現於發育中的組織,因在腫瘤組織中表現量高,近年來研究當作癌症的生物標誌物。無脊椎動物中僅以一種形態存在 (PRL-1),演化為脊椎動物後分為三型 (ptp4a1、ptp4a2和ptp4a3)。三型 ptp4a 間的胺基酸序列相似度很高,本論文研究的脊椎動物斑馬魚,其中 ptp4a1和ptp4a2 有 81% 相似。以原位雜交法觀察斑馬魚胚胎時期 mRNA 的表現,ptp4a1 於12小時至三天的表現量最高,多表現於腦部 (包括終腦、間腦、中腦、小腦和後腦)、眼睛 (包括視網膜色素上皮層、外叢層、內叢層和神經纖維層)、耳包、鰭等部分。而 ptp4a2 則是在胚囊期至三天的表現量均高,大部份表現於心肌、肌節、肝臟、腸道、原腎管、氣動管、鰾、鰭、下顎及眼睛的水晶體外圈等位置。接著利用顯微注射反股寡核苷酸 (morpholino) 的方式,抑制內生性 ptp4a1 和 ptp4a2 轉譯。個別抑制 ptp4a1 和 ptp4a2 可觀察到基因缺陷後造成圍心腔腫大及細胞堆積的情形,同時抑制 ptp4a1 和 ptp4a2 外觀上的缺陷更加顯著。以F59 標記抗體及 cmlc2 探針觀察心臟肌肉,可知基因缺失會造成心臟肌肉形狀改變。從基因缺失會造成細胞增生訊號下降,但沒有細胞凋亡訊號產生等結果推測,ptp4a1 和 ptp4a2 缺失會造成細胞增生受阻,以至於心臟肌肉無法正常發育,心肌折疊不完全,產生心肌畸形。此外,ptp4a1 和 ptp4a2 缺失還會導致斑馬魚感覺器官,側線神經節發育異常,無法如同野生種發育出完整的側線神經節。由上述的實驗結果可知,ptp4a1 和 ptp4a2 在脊椎動物斑馬魚身上表現位置不同, ptp4a1 多表現於腦及眼睛,ptp4a2 表現於肌肉和心臟、肝臟、腸道等多種內臟組織中。胚胎時期若 ptp4a1 和 ptp4a2 缺陷,會影響到細胞增生以至於心臟肌肉發育不完全,且影響細胞移動能力,導致側腺神經節發育異常。由此可知,ptp4a1 和 ptp4a2 對斑馬魚胚胎的發育,是重要的環節之一。
英文摘要 Protein tyrosine phosphatase 4A (ptp4a) family not only affect cell growth, division, migration and differentiation but serve as a “biomarker” of cancer in recent studies. Instead of only one type (PRL-1) in vertebrates, ptp4a family contains three members (ptp4a1, ptp4a2, and ptp4a3) with high sequence similarities. In this study, we focused on zebrafish ptp4a1 and ptp4a2 genes sharing 81% similarity. We performed in situ hybridization to observe the expression of ptp4a1 and ptp4a2 during zebrafish embryonic development. ptp4a1 was abundant from 12-hpf to 3-dpf, and mainly found in brain (tectum, tegmentum, telencephalon, diencephalon, mesencephalon, cerebellum, and metencephalon), eyes (retinal pigment epithelium, iris, outer plexiform layer, inner plexiform layer and nerve fiber layer), otic vesicle, and fin. On the other hand, ptp4a2 was abundant from 1-cell stage to 3-dpf, and was mainly distributed in myocardium, liver, fin, gut, myotomes, pronephric duct, pneumatic duct, swim bladder, arch and the outer region of the lens. Upon injection of antisense morpholino (ptp4a1-MO or ptp4a2-MO), pericardial edema and cell accumulation were observed in ptp4a1 or ptp4a2 knockdown embryos. Furthermore, co-injection of ptp4a1-MO and ptp4a2-MO resulted in even more significant defect. Heart malformation was revealed in ptp4a1/2 double knockdown embryos, based on immunostaining with muscle-specific F59 antibody and in situ hybridization with heart-specific cmlc2 probe. On the other hand, ptp4a1/2 double knockdown would result in disrupted neuromast development. In addition, such knockdown would decrease cell proliferation, but not lead to apoptosis. In summary, ptp4a1 and ptp4a2 showed differential expression patterns in zebrafish embryos: ptp4a1 was mainly found in brain and eyes, whereas ptp4a1 was mainly observed in muscle, heart, liver, gut and internal organs. Our knockdown data revealed that ptp4a1 and ptp4a2 affected cell proliferation and migration, leading to defects in zebrafish heart and neuromast development.
論文目次 授權書
口試委員審議通過簽名單
謝誌-----------------------------------------------------------------------------I
中文摘要----------------------------------------------------------------------II
英文摘要---------------------------------------------------------------------III
目錄---------------------------------------------------------------------------IV
圖表目錄-------------------------------------------------------------------VIII
第一章 前言------------------------------------------------------------------1
1-1酪胺酸磷酸水解酶(protein tyrosin phospatase genes, PTPs)------------------1
1-2第四類酪胺酸磷酸水解酶(protein tyrosin phospatase 4A, ptp4a)-----------2
1-3第四類酪胺酸磷酸水解酶的結構------------------------------------------------3
1-4第四類酪胺酸磷酸水解酶在正常組織中的表現------------------------------4
1-5第四類酪胺酸磷酸水解酶在腫瘤及病變組織中的表現---------------------7
1-6第四類酪胺酸磷酸水解酶的表現及影響細胞週期--------------------------11
1-7第四類酪胺酸磷酸水解酶在發育中的角色-----------------------------------15
1-8斑馬魚為模式物種研究第四類酪胺酸磷酸水解酶的優勢-----------------16

第二章 材料與方法--------------------------------------------------------18
2-1斑馬魚胚胎收集 (Embryo collection)------------------------------------------18
2-2斑馬魚放缸飼養 (Fish breeding)------------------------------------------------18
2-3斑馬魚胚胎固定、脫水、保存 (Embryo fixation)------------------------------18
2-4斑馬魚胚胎 RNA 的萃取及cDNA的合成-----------------------------------19
2-5勝任細胞 (Competent cell) 的製備---------------------------------------------20
2-6細胞轉形作用(Transformation)--------------------------------------------------21
2-7小量質體萃取 (Isolation of Plasmid DNA)------------------------------------21
2-8聚合酶鏈鎖反應 (Polymerase Chain Reaction, PCR)------------------------22
2-9核酸的接合反應 (DNA ligation)------------------------------------------------22
2-10合成探針 (Riboprobe)-----------------------------------------------------------23
2-11原位雜交法 (Whole-mount in situ hybridization)---------------------------24
2-12抗體染色 (Immunostaining)----------------------------------------------------25
2-13 TUNEL Assay---------------------------------------------------------------------27
2-14側線神經節活體螢光染色------------------------------------------------------28
2-15顯微注射實驗 (Morpholino antisense oligouncleotide injection for knockdown) ------------------------------------------------------------------------------28
2-16樣品包埋及切片 (Embedding and Cryosectioning)-------------------------29
2-17顯微照相系統及序列分析軟體------------------------------------------------29

第三章 結果-----------------------------------------------------------------30
3-1斑馬魚的 ptp4a 胺基酸序列比對及演化分析圖----------------------------30
3-2各時期之斑馬魚胚胎以原位雜交法 (whole-mount in situ hybridization) 確定ptp4a1 的訊號表現位置--------------------------------------------------------32
3-3各時期之斑馬魚胚胎以原位雜交法確定ptp4a2的訊號表現位置--------35
3-4透過顯微注射 ptp4a1 & ptp4a2 morpholino 抑制 ptp4a1 & ptp4a2 的轉譯所造成之影響------------------------------------------------------------------------37
3-5 ptp4a1 & ptp4a2 morpholino 注射後的存活率及變異率-------------------38
3-6以F59免疫抗體染色法探討 ptp4a1 & ptp4a2 knockdown 後,對心臟肌肉造成的影響---------------------------------------------------------------------------40
3-7以 cmlc2 mRNA 探針,進行原位雜交法探討 ptp4a1 & ptp4a2 knockdown 後對心臟造成的影響---------------------------------------------------40
3-8以TUNEL Assay探討 ptp4a1&ptp4a2 knockdown對細胞凋亡的影響---------------------------------------------------------------------------------------------42
3-9以 Phospho-Histone H3 抗體染色探討 ptp4a1 & ptp4a2 knockdown 對細胞增生的影響------------------------------------------------------------------------43
3-10 ptp4a1 & ptp4a2 knockdown 對斑馬魚胚胎側線神經節的影響--------44

第四章 討論-----------------------------------------------------------------46
4-1 ptp4a1 & ptp4a2 於脊椎動物中具有高度保留性---------------------------46
4-2 ptp4a1 & ptp4a2 缺失導致斑馬魚胚胎的側線與心臟發育不良之可能原因------------------------------------------------------------------------------------------48
4-3 ptp4a1 & ptp4a2 影響細胞移動之可能原因---------------------------------51
4-4 ptp4a1 & ptp4a2 影響細胞生長之可能原因---------------------------------53
4-5 總結----------------------------------------------------------------------------------54

第五章 參考文獻-----------------------------------------------------------56
圖表---------------------------------------------------------------------------62
附錄---------------------------------------------------------------------------87

圖表目錄
圖一 . 斑馬魚的 ptp4a 基因體結構圖。------------------------------------------63
圖二 . 斑馬魚的 ptp4a 胺基酸序列比對及演化樹分析圖。------------------64
圖三 . 四細胞至三天大之斑馬魚以原位雜交法確定ptp4a1 的訊號表現位置。-----------------------------------------------------------------------------------------67
圖四 . 四天至七天大之斑馬魚以原位雜交法確定ptp4a1 的訊號表現位置。----------------------------------------------------------------------------------------------68
圖五 . 四細胞至三天大之斑馬魚以原位雜交法確定ptp4a2 的訊號表現位置。-----------------------------------------------------------------------------------------69
圖六 . 四天至七天大之斑馬魚以原位雜交法確定ptp4a2 的訊號表現位置。----------------------------------------------------------------------------------------------70
圖七 . 斑馬魚各個時期以原位雜交法後,以flat mount 及冷凍切片比較 ptp4a1和ptp4a2的訊號表現位置。--------------------------------------------------71
圖八 . 斑馬魚胚胎之野生種 (WT) 、ptp4a1 morphant、ptp4a2 morphant 及 ptp4a1+ ptp4a2 morphant 的表現型。-----------------------------------------------74
圖九 . 斑馬魚胚胎之F59免疫抗體染色觀察心臟表現型態。-----------------76
圖十 . 斑馬魚胚胎之cmlc2 mRNA 探針觀察心臟變異。----------------------77
圖十一 . 斑馬魚胚胎進行 TUNEL Assay,觀察細胞凋亡的情況。----------80
圖十二 . 斑馬魚胚胎之 Phospho-Histone H3 抗體染色,觀察細胞增生的情況。-----------------------------------------------------------------------------------------81
圖十三 . 斑馬魚胚胎之 RHE487 側線染色,觀察側線生長狀況。----------82
表一. 斑馬魚的 ptp4a1、ptp4a2、 ptp4a3 及果蠅的 PRL-1 之胺基酸序列相似性。-----------------------------------------------------------------------------------83
表二. 斑馬魚的 ptp4a1 與不同種類動物之胺基酸序列相似性。------------83
表三. 斑馬魚的 ptp4a2 與不同種類動物之胺基酸序列相似性。------------83
表四. 斑馬魚的 ptp4a3 與不同種類動物之胺基酸序列相似性。------------84
表五. 斑馬魚之 ptp4a1 / ptp4a2/ ptp4a3與脊椎動物間的統整總表。--------85
表六. 斑馬魚胚胎注射不同濃度之ptp4a1和ptp4a2反股寡核苷酸(morpholino antisense oligonucleotides)的存活率及變異率。--------------------86
附錄
附表一、ptp4a 表現於腫瘤組織。--------------------------------------------------88
附圖一、負回饋抑制 p53 的兩種路徑。--------------------------------------------89
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