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研究生:桂子惠
研究生(外文):Tzu Hui Kuei
論文名稱:cyclinD1參與調控斑馬魚胚胎血液系統以及神經系統的發育
論文名稱(外文):cyclin D1 regulates zebrafish embryonic hematopoietic and neural development
指導教授:鄭邑荃
指導教授(外文):Y. C. Cheng
學位類別:碩士
校院名稱:長庚大學
系所名稱:生物醫學研究所
學門:工程學門
學類:生醫工程學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
論文頁數:77
中文關鍵詞:斑馬魚造血神經生成細胞週期細胞命運
外文關鍵詞:zebrafishhematopoiesisneurogenesiscell cyclecell fate
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在發育的過程中,細胞的遷移、分化等過程是被嚴密調控的。其中如cyclin/cdk這些細胞週期的調控分子,是否也參與在調控細胞的分化,目前仍然沒有足夠的證據。我在斑馬魚資料庫中找到了三個與哺乳類中D-type cyclin同源的基因,分別為cyclin D1、cyclin D2以及cyclin D3。我利用whole mount in situ hybridization的方式觀察到,cyclin D1在不同時期的胚胎中表現在許多特定組織,包括造血系統以及神經系統,而抑制cyclin D1的表現後,會造成這兩個系統發育不正常,反應出cyclin D1可能在這兩個系統的發育中扮演著重要的角色。我利用mopholino去抑制其表達量後,發現scl、gata1以及rag1這三個血液細胞標定基因表現量皆下降。同樣利用MO抑制cyclin D1在轉基因魚Tg(Fli:GFP)中的表現,發現其並不會影響到管脈生成以及血管新生。另外在神經系統方面,將抑制cyclin D1表現後的胚胎利用後腦分節的marker EphA4、神經細胞的marker Hu、deltaA、islet、神經膠細胞的marker zrf1以及神經軸突的marker acetyl tubulin進行染色,並無法觀察到很明顯的改變,顯示該基因並非很直接地參與神經系統的發育,然而cyclin D1在中樞神經系統有高度的表達,且由於cyclin D2以及D3與D1具有很高的相似性,顯示這三者可能具有相似的功能,這樣的結果也可能是由於gene redundancy所造成。而在活化了Akt訊息傳遞路徑的胚胎當中,我發現在中樞神經系統以及血液系統中cyclin D1的表現量有明顯的上升,且無異位的表達。以上的結果顯示,cyclin D1參與在班馬魚胚胎血液以及神經系統的生成當中,並對於調控血球幹細胞的生成以及神經幹細胞的維持扮演重要的角色,但並不參與調控這些細胞的分化。並且在這兩個系統發育時,Akt訊息可能是調控cyclin D1表現量之一重要途徑。
The generation of different cell types including neural cells needs precise control over cell cycle exit. Whether the cell cycle regulators can also regulate cell differentiation is still not clarified. I isolated the cell cycle regulators, cyclin D1, cyclin D2 and cyclin D3 from the zebrafish genome. These genes show high homology to mammalian cyclin D and expression analysis of cyclin D1 in particular showed a dynamic pattern in the developing hematopoietic system and central nervous system (CNS), which suggests that cyclin D1 may play an important role in these developing tissues. Therefore I knocked down the expression of cyclin D1 by morpholino oligos, and found that the expression of scl, gata1 and rag1 were reduced in the morphants. Under the same condition, the MO injection did not affect vasculargenesis and angiogenesis analyzed with Tg(Fli:GFP) embryos. Further I used segmental marker EphA4, post-mitotic neuronal marker Hu, proneural marker deltaA, specific neuronal marker islet, glial marker zrf1, and neurite marker acetyl tubulin to perform immunohistochemistry experiments. The results did not show obvious changes in the neural patterning or the amount of neurons, suggesting that cyclin D1 may not be involved in neurogenesis. However, given the fact that cyclin D1 is highly expressed in the CNS, this result can be explained by gene redundancy since cyclin D2 and D3 are highly identical to cyclin D1 and therefore may share the similar functions. Interestingly the expression of cyclin D1 were increased in the hematopoietic and neural systems after activating Akt signaling pathway, with no ectopic expression, suggesting that the expression and role of cyclin D1 in zebrafish hematopoietic and neural development may be govered by Akt signaling pathway.
Table of Contents
指導教授推薦書
口試委員會審定書
授權書 III
致謝 IV
摘要 V
TABLE OF CONTENTS VII
TABLE OF ABBREVIATIONS IX
TABLE AND FIGURE LIST XI
CHAPTER I – INTRODUCTION 1
CHAPTER II – MATERIALS AND METHODS 6
MATERIALS 6
2.1 ANIMAL MODEL 6
METHODS 6
2.2 FISH LINE 6
2.3 PLASMID CONSTRUCTS 6
2.4 SYNTHESIS OF RNA PROBES 7
2.5 WHOLE MOUNT IN SITU HYBRIDYZATION 8
2.6 CYOSECTION FOR HISTOLOGICAL ANALYSIS 9
2.7 MICROINJECTION 9
2.8 IMMUNOHISTOCHEMISTRY AND FLUORESCENCE DETECTION 10
2.9 TDT-MEDIATED DUTP NICK END LABELING (TUNEL) ASSAY 11
CHAPTER III – RESULTS 12
3.1 ISOLATION OF TWO PARALOGUS D CYCLINS IN ZEBRAFISH 12
3.2 EXPRESSION PATTERNS OF CYCLIN D2 AND D3 IN THE ZEBRAFISH EMBRYOS 12
3.3 DEFECTS CAUSED BY CYCLIN D1 MORPHOLINO KNOCKDOWN 13
3.3.1 Circulation defects caused by cyclin D1 morpholino knockdown 14
3.3.2 Hematopoietic abnormality in cyclin D1 knockdown embryos 15
3.3.3 cyclin D1 in vasculogenesis and angiogenesis 18
3.3.4 Embryos have fewer neural precursor cells caused by cyclin D1 morpholino knockdown 18
3.3.5 Knockdown of cyclin D1 in vivo affect neurites outgrowth in the hindbrain 21
3.4 CYCLIN D1COULD BE REGULATED BY AKT SIGNALING PATHWAY IN THE DEVELOPING HEMATOPOIETIC AND NERVOUS SYSTEM 22
CHAPTER IV – DISCUSSION 24
4.1 THE DEFECTS OF THE CYCLIN D1 MORPHANTS IN THE BLOOD AND CIRCULATORY SYSTEM 24
4.2 THE DEFECTS OF THE CYCLIN D1 MORPHANTS IN THE NERVOUS SYSTEM 26
REFERENCE LIST 31
APPENDIX 63

Table and Figure List
TABLE 1 TISSUES IN DIFFERENT STAGES EMBRYOS EXPRESS CYCLIN D1 MRNA . 40
TABLE 2 IDENTITY BETWEEN CYCLIN D1, CYCLIN D2, CYCLIN D3 AND DIFFERENT CYCLIN FAMILY MEMBERS. 42

FIGURE 1 EXPRESSION PATTERN OF CYCLIN D1 IN ZEBRAFISH EMBRYOS AT 10 SS, 13 SS AND 17 SS. 38
FIGURE 2 EXPRESSION PATTERN OF CYCLIN D1 IN ZEBRAFISH EMBRYOS AT 18 SS, PRIM-5 STAGE (24 HPF) AND PRIM-15 STAGE (36 HPF). 39
FIGURE 3 EXPRESSION PATTERN OF CYCLIN D1 IN HEAD 41
FIGURE 4 SIMPLE REPRESENTATION OF POLYPEPTIDE CHAIN AND CYCLIN DOMAIN OF CYCLIN FAMILY. 42
FIGURE 5 ILLUSTRATION OF PCS2+-CYCLIN D2 AND PCS2+-CYCLIN D3 CONSTRUCTS. 43
FIGURE 6 MO2 EFFICIENTLY CAUSES CYCLIN D1 MRNA MISSPLICING 44
FIGURE 7 EXPRESSION OF CYCLIN D1 AND PAX-B IN MESODERM IS SPECIFIC AND MUTUALLY EXCLUSIVE. 45
FIGURE 8 PHENOTYPE OF CYCLIN D1-DEFICIENT EMBRYOS 46
FIGURE 9 THE HEART RATE (HEART BEATS/MINS) IN EMBRYOS INJECTED BOTH MO WERE SIGNIFICANTLY DIFFERENT FROM THE CONTROL EMBRYOS. 47
FIGURE 10 CYCLIN D1 MRNA COULD PARTIALLY RESCUE DEFECTIONS CAUSED BY MO1 48
FIGURE 11 THE EXPRESSION OF SCL IN THE ANTERIOR LATERAL MESODERM OF CONTROL AND CYCLIN D1 DEFICIENT EMBRYOS 49
FIGURE 12 THE EXPRESSION OF SCL IN THE POSTERIOR LATERAL MESODERM OF CONTROL AND CYCLIN D1 DEFICIENT EMBRYOS 50
FIGURE 13 THE EXPRESSION OF GATA1 IN THE POSTERIOR LATERAL MESODERM OF CONTROL AND CYCLIN D1 DEFICIENT EMBRYOS 51
FIGURE 14 THE EXPRESSION OF RAG1 IN CONTROL AND CYCLIN D1 DEFICIENT EMBRYOS 52
FIGURE 15 CYCLIN D1 KNOCKDOWN EFFECTS CELL PROLIFERATION IN THE ZEBRAFISH EMBRYOS. 53
FIGURE 16 CELL APOPTOSIS, VASCULOGENESIS AND ANGIOGENESIS OF TG(FLI:GFP) EMBRYOS 55
FIGURE 17 AMINO ACID SEQUENCE ALIGNMENT SHOWS HIGH SIMILARITY BETWEEN ZEBRAFISH AND OTHERS MAMMALIAN OTHOLOGS AROUND THREONINE 156 56
FIGURE 18 CYCLIN D1 KNOCKDOWN CAUSE DECREASING OF NEURAL PRECURSORS IN THE ZEBRAFISH EMBRYOS. 57
FIGURE 19 CYCLIN D1 KNOCKDOWN ALSO AFFECT THE AMOUNT OF NEURITES IN THE HINDBRAIN. 58
FIGURE 20 CYCLIN D1 KNOCKDOWN DOES NOT AFFECT THE NEURITES OUTGROWTH OF THE MAUTHNER NEURONS. 59
FIGURE 21 CYCLIN D1 KNOCKDOWN ALSO DOES NOT AFFECT THE NEURITES OUTGROWTH OF THE SPINAL CORD NEURONS. 60
FIGURE 22 ANALYSIS OF CONSERVED NONCODING SEQUENCE BLOCKS OF THE CYCLIN D1 GENES. 61
FIGURE 23 ACTIVATING THE AKT SIGNALING PATHWAY UP REGULATES CYCLIN D1 TRANSCRIPTS IN CNS AND ICM. 62
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