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系統識別號 U0026-3007201321072500
論文名稱(中文) 建立具誘發性葉酸缺乏之斑馬魚模式並用以探討因葉酸缺乏所導致胚胎發育異常之機轉
論文名稱(英文) An inducible folate deficient model in zebrafish reveals impaired neurogenesis and hematopoiesis caused by folate deficiency
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 101
學期 2
出版年 102
研究生(中文) 高增婷
研究生(英文) Tseng-Ting Kao
學號 S58971455
學位類別 博士
語文別 英文
論文頁數 74頁
口試委員 指導教授-傅子芳
口試委員-許桂森
口試委員-曾淑芬
口試委員-陳曜鴻
口試委員-蔣恩沛
中文關鍵字 葉酸缺乏  γ-穀氨酸水解酶  斑馬魚  出生缺陷 
英文關鍵字 folate deficiency  γ–glutamyl hydrolase  zebrafish  birth defects 
學科別分類
中文摘要 葉酸是胚胎發育必需的營養素。懷孕婦女未能攝取充足的葉酸將會增加其胎兒獲得先天性神經管缺陷的風險。然而對於葉酸缺乏造成的出生缺陷的作用機轉還未完全了解。斑馬魚是一個研究發育生物學有利的動物模式,但是要利用控制魚的飲食來造成葉酸缺乏卻極其困難。在本研究中利用熱休克啟動子控制γ-穀氨酸水解酶的異位表達,建立一誘發性葉酸缺乏斑馬魚動物模式。γ-穀氨酸水解酶的功能是藉由去除葉酸結構上鍵結的多穀氨酸來促進細胞內葉酸的運送。我們發現在此動物模式中葉酸缺乏的嚴重程度和γ-穀氨酸水解酶的表現量呈正相關。且葉酸缺乏的斑馬魚胚胎展現了臨床相關疾病特徵,包括:異常的神經管閉合、頭臉部及眼睛的發育異常和受損的造血功能。這些發育缺陷藉由補充葉酸都能夠部分恢復,顯示葉酸缺乏造成疾病產生的因果特異性。我們也發現在葉酸缺乏的胚胎中神經細胞和後側線基原細胞的正常遷移受到阻擾,進一步探討顯示氧化壓力和細胞外訊號調節激酶的訊號路徑很可能參與在葉酸缺乏導致的先天性異常。以上的結果顯示此新發展出的動物模式能提供做為另一實驗脊椎動物平台應用於活體研究葉酸缺乏相關致病機轉。
英文摘要 Folate is an essential nutrient, which is especially important for embryogenesis. Insufficient folate intake in pregnant women was reported to increase the risk of delivering the fetus with congenital defects including neural tube defects. However, the etiology for folate deficiency-associated birth defects is not fully understood. Zebrafish is a powerful model organism for developmental biology research. However, to establish a folate deficient zebrafish via dietary control is difficult and impractical. In present study, we established a heat-shock induced folate deficient zebrafish model by ectopically expressing γ–glutamyl hydrolase (GGH), the enzyme removing the polyglutamyl moiety of folate and facilitating the exportation of intracellular folate. We found that the extent of folate deficiency in GGH-overexpressing transgenic embryos was positively correlated to the expression level of GGH. These folate deficient embryos exhibited the characteristic phenotypes of folate deficiency, including impeded neural tube closure, craniofacial and ophthalmic abnormalities and impaired hematopoiesis. These anomalies were partly reversed by folate supplementation, suggesting a cause-and-consequence specificity. Our results also showed that the migration of neural crest cells and posterior lateral line primordia were obstructed in folate deficient transgenic embryos. Further investigation suggested that oxidative stress and ERK signal pathway were likely to be involved in the occurrence of abnormalities caused by folate deficiency. Our results suggested that this newly developed model can serve an alternative platform of vertebrate for studying folate-deficiency associated pathogenesis in vivo.
論文目次 摘要 I
Abstract II
Acknowledgements III
Contents IV
Contents of tables and figures VIII
Abbreviations X
I. Introduction 1
1.1 General introduction: Folate and one carbon metabolism (OCM) 1
1.1.1 Structure of folate 1
1.1.2 Biological availability 1
1.1.3 OCM and related biosynthetic pathways 2
1.1.4 Gamma gl utamyl hydrolase 3
1.1.5 Folate de ficiency-associated pathologies 3
1.2 Neural tube defects (NTD) 4
1.3 Current folate deficient models 5
1.4 Zebrafish model 6
1.4.1 In ge neral 6
1.4.2 Advantages in folate related studies 6
1.4.3 Limitations in folate related studies 7
II. Rationale of this study 8
III. Specific aims 8
IV. Materials and methods 9
4.1 Constructs 9
4.2 Transgenic lines generation and fish care 10
4.3 Heat shock condition 11
4.4 Compounds treatment for embryos and larvae 11
4.5 Folates content analysis of embryos and cultured cells 12
4.6 Whole mount in situ hybridization 12
4.7 Neuromast staining with 4-di-2-Asp 13
4.8 Hemoglobin staining with O-dianiside 13
4.9 Epiboly analysis 14
4.10 Hard bone staining with Calcein dye 14
4.11 Cryosection and histochemistry 14
4.12 Western blotting 15
4.13 Cell culture and transfection 15
4.14 Statistics 16
V. Results 17
5.1 Ectopic expression of GGH in cytosol reduced intracellular folate level 17
5.2 Endogenous GGH was hardly detectable in wild type embryos during early embryogenesis 17
5.3 The establishment of inducible folate deficiency zebrafish lines 18
5.3.1 Tg (zhs70:EGFP-GGH) 18
5.3.2 Tg (lfabp:mCherry;zhs70:EGFP-GGH) 18
5.3.3 Tg (zhs70:EGFP-GGHC108A) 19
5.4 Characterizations of folate deficiency zebrafish lines 19
5.4.1 The establishment of heat shock protocol (39 ℃, 1hour) 19
5.4.2 The correlations among green fluorescence intensity, EGFP-GGH protein levels, and folate deficiency in FD embryos 20
5.5 The neurulation period was sensitive to folate deficiency and critical for folate deficiency- associated abnormalities 21
5.6 Phenotypic characterizations on folate deficient (FD) embryos 21
5.6.1 FD impeded neural tissue formation 21
5.6.2 FD caused hematopoietic anomaly 22
5.6.3 FD impeded the development of neural crest cells derived non-neural tissues 23
5.7 Folate supplementation rescued the abnormalities in FD embryos 23
5.8 Folate deficiency inhibited cell migration 24
5.8.1 The migration of NCCs was disrupted in FD embryos 24
5.8.2 The participant of Wnt signaling 25
5.8.3 The interrupted (collective) cell migration in FD embryos 25
5.9 ERK activation attributed to the folate deficiency-associated hematopoietic anomalies 27
VI. Discussion 28
VII. Conclusion 35
VIII. References 36
IX. Tables 47
X. Figures 50
XI. Appendices 68
XII. Author 74




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