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研究生:林哲毅
研究生(外文):Che-Yi Lin
論文名稱:利用正向及反向遺傳學研究斑馬魚心臟之型態形成
論文名稱(外文):Forward and reverse genetic studies in zebrafish cardiac patterning
指導教授:黃聲蘋
指導教授(外文):Sheng-Ping L. Hwang
學位類別:博士
校院名稱:國立臺灣海洋大學
系所名稱:生物科技研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2013
畢業學年度:101
語文別:英文
論文頁數:90
中文關鍵詞:斑馬魚心臟發育心二分支左右不對稱
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脊椎動物胚胎發育過程中,心臟是第一個形成且具有功能的器官。心臟的正常發育,包含了心臟前驅細胞的移動、心肌及心內皮細胞的分化及生長、心房心室的形成等過程皆受到嚴謹且複雜的基因調控,這些過程一旦出錯將導致心臟不正常的發育。本論文使用斑馬魚為模式生物來研究心臟發育過程中有關心臟前驅細胞移動及後續心臟彎曲等形態形成之調控機制。斑馬魚為硬骨魚類,其胚胎發育中基因的調控機制與哺乳類相似,且具有包括性成熟時間短、單次產卵數目高、魚體透明易於觀察、基因組已完全解碼、體外受精利於基因操作、基因操作工具多等優點,使得斑馬魚近年來成為一研究脊椎動物遺傳與發育的良好模式生物。
本論文包括兩部分,分別利用正、反向遺傳學來研究斑馬魚心臟發育過程中有關心臟前驅細胞移動及後續心臟彎曲等形態形成之調控機制。在第一部份正向遺傳學方面,我們利用ENU (ethylnitrosourea)化學突變劑來處理BMP4:EGFP螢光魚,篩選出一隻心臟發育異常的突變斑馬魚(s1pr2as10)。大部分的突變魚在受精後28小時前(28 hpf)的胚胎,可觀察到具有兩顆獨立的心臟,而過了28 hpf後,此兩顆心臟會逐漸部分融合在一起,而形成類似兩生類之兩心房一心室的心臟。基因定位結果顯示突變魚中有一段外來的序列插入在edg5/mil基因座的intron1上造成該基因表現下降。此外,我們發現將s1pr2as10突變魚胚胎培養在較低的溫度 (22.5℃) 時,發育到72 hpf的胚胎會形成正常的1心房1心室的心臟,且具有正常的血液循環。另外因注射gata5或bon專一性反意morpholino寡核酸所產生兩側心臟的胚胎,其心臟細胞移動的缺陷,亦能因培養在22.5℃的溫度下而被拯救。我們利用DNA microarray、digital基因表現分析、反意morpholino寡核酸弱化及mRNA或蛋白質過度表現等方式,發現fibronectin1,tenascin-c以及tenascin-w等細胞外基質基因對於低溫救回兩顆心臟是必須的。此外我們亦發現低溫可能會引發過氧種類(reactive oxygen species)而參與低溫救回兩顆心臟的過程。
在第二部份反向遺傳學方面,我們利用反意morphlino寡核苷酸基因弱化來探討斑馬魚Krüppel like factor 8 (Klf8)轉錄因子在心臟彎曲時所扮演的角色。在注射klf8專一性的反意morphlino寡核苷酸的72 hpf胚胎中,其心臟呈現拉直的情形。18-22體節klf8 morphant胚胎中,應表現在左側側板中胚層、間腦或心臟的spaw,lft1,lft2以及pitx2其mRNA的表現呈現下降或消失的情形。相反地,我們過度表現klf8 mRNA觀察到大部份被注射的胚胎中Nodal訊息傳遞成員基因皆在胚胎的左右兩側表現。另外我們發現斑馬魚spaw intron1中具有不同魚類高度保守的151 bp序列,其中分別含有兩個FoxHI及SMAD結合序列。將此保守的序列接在spaw基本啟動子5端(spaw bp_In1),來驅動綠色螢光蛋白質的表現時,發現大部份被注射的18-20體節胚胎表現綠色螢光蛋白質在左側側板中胚層。同時一同注射Spaw bp_In1質體及klf8 mRNA,可以驅使更多的胚胎中綠色螢光蛋白質表現在側板中胚層,而在共同注射klf8反意morphlino寡核苷酸及Spaw bp_In1質體的胚胎中,則幾乎沒有綠色螢光蛋白質的表現。這些實驗結果顯示斑馬魚Klf8轉錄因子會調控spaw在左側側板中胚層的表現,進而調節心臟的左右不對稱的形態形成。

Heart is the first functional organ to form during vertebrate development. The complex gene regulation of the coordinated migration of bilateral cardiomyocytes, the differentiation of myocardium and endocardium, and the formation of atrium and ventricle are essential for the heart formation. Disruption of these processes result in the heart malformation. In this study, we used zebrafish as an animal model to investigate the gene regulatory mechanisms involved in myocardial migration, and heart looping. There are several advantages using teleost like zebrafish as an animal model, including similar gene regulatory mechanism to mammals, short sexual maturation time, abundant egg production, transparent body for easy observation, fully decoded genome, in-vitro fertilization for convenient genetic manipulation, and many available genetic tools. With these advantages, zebrafish became an excellent animal mode to study vertebrate genetics and development in recent years.
This thesis was divided into two parts. We respectively use forward and reverse genetic approaches to investigate gene regulatory mechanisms involved in myocardial migration, and heart looping. In the first part, through screening of Tg(-7.5bmp4:GFP)as1 transgenic zebrafish line treated with ethylnitrosourea, we isolated a mutant with heart morphogenetic defects, named s1pr2as10. Mutant embryos exhibited cardia bifida prior to 28 hours post-fertilization (hpf). Although the bilateral hearts of the mutants gradually fused together, this resulting formation of two atria and one tightly-packed ventricle. By performing positional cloning, we identified a large insertion in the first intron of mil/edg5 resulting in decreased expression of mil/edg5. Interestingly, cardia bifida of s1pr2as10 embryos could be rescued and normal circulation could be restored by incubating the embryos at low temperature (22.5 °C). Most s1pr2as10 embryos exhibited only one atrium and one ventricle with normal circulation when raised at low temperature. Rescue was also observed in gata5 and bon cardia bifida morphants raised at 22.5 °C. We conducted DNA microarrays, digital gene expression analyses, antisense morpholino knockdown, mRNA or protein overexpression experiments and found that fibronectin 1, tenascin-c and tenascin-w are required for the mitigation of cardia bifida. Furthermore, we found that low temperature may increase the ROS level that allows the mitigation of cardia bifida in s1pr2as10 mutant embryos.
In the second part, we knock down klf8 expression by microinjection of klf8 morpholino antisense oligomer (MO) to investigate the role of klf8 in heart looping. klf8 morphants did not establish normal heart looping at 72 hpf. Expression levels of members of Nodal signaling including spaw, lft1, lft2 and pitx2 were significantly decreased in the left lateral plate mesoderm (LPM), diencephalon or heart of klf8 morphants at 18- 22 somite stage. On the other hand, overexpression of klf8 mRNA resulted in bilateral expression of Nodal signaling genes in these tissues. We identified a 151 bp sequence in the intron 1 of spaw, which is conserved in teleost. This sequence contained two SMAD and two FoxH1 binding motifs. We then cloned the 151 bp conserved region upstream of the spaw basal promoter (spaw bp_In1) and found that most of embryos injected with this construct expressing EGFP in the left LPM during the 18-20 ss. Overexpression of klf8 mRNA resulted in increased percentage of embryos expressing EGFP in the LPM at 18 ss, while co-injection of spaw bp_In1 construct and klf8 morpholino caused a reduction in percentage of embryos expressing EGFP in the left LPM. Overall, our study demonstrates that zebrafish Klf8 regulates heart looping via promoting the expression of spaw.

Abstract (Chinese) I
Abstract (English) III
Contents V
List of tables VI
List of figures VII
Chapter 1 Low temperature mitigate cardia bifida in zebrafish embryos 1
1.1 Abstract 1
1.2 Introduction 2
1.3 Materials and Methods 5
1.4 Results 9
1.5 Discussion 17
1.6 Tables 20
1.7 Figures 22
1.8 References 42
Chapter 2 The discovery of spaw left-side specific enhancer and the regulation of spaw asymmetric expression by zebrafish Klf8 47
2.1 Abstract 47
2.2 Introduction 48
2.3 Materials and Methods 50
2.4 Results 53
2.5 Discussion 57
2.6 Tables 59
2.7 Figures 61
2.8 References 77

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