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研究生:鍾欣怡
研究生(外文):Hsin-yi Chung
論文名稱:斑馬魚低氧誘發因子hif基因對胚胎頭骨發育的影響
論文名稱(外文):The zebrafish hypoxia-inducible factor (hif) and head skeleton development
指導教授:胡清華胡清華引用關係
指導教授(外文):Chin-Hwa Hu
學位類別:碩士
校院名稱:國立海洋大學
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:2003
畢業學年度:91
語文別:中文
論文頁數:91
中文關鍵詞:斑馬魚低氧誘發因子頭骨
外文關鍵詞:hypoxia-inducible factorhead skeletonzebrafish
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低氧誘發因子(hypoxia-inducible factor,HIF)為一群具有bHLH-PAS此保守區域的基因調控蛋白,最主要的功能在調節生物體內供氧的平衡(oxygen homeostasis)。在最近的研究中,發現此低氧誘發因子參與著胚胎發育的過程,當此蛋白形成異偶合體結構(heterodimer)時,具有調控下游基因的能力。細胞內缺氧時,低氧誘發因子(hypoxia-inducible factor,包括hif 1α、 hif 2α、 hif 3α)會與另一bHLH-PAS蛋白ARNT(aryl hydrocarbon receptor translocator,亦稱為hif-1β)形成安定的蛋白異偶合體結構,藉由辨識目標基因啟動子上缺氧感應序列(HRE,hypoxia response element)調控下游基因的表現,如VEGF、GLUT1、 NOS 、EPO 、LDH-A,目前已知超過40種以上的基因受到調控(Semenza, 2002)。
先前,本實驗室成功的在斑馬魚(zebrafish)胚胎選殖出兩段hif基因,包括hif 1α以及hif 3α,利用RNA全覆式原位雜交法(whole mount in situ hybridization)觀察,顯示在咽胚期兩者RNA表現重疊出現在頭部感覺器官的耳囊、 嗅基板 、中腦以及後腦、 髓腦。此外hif 1α在36∼48hpf會表現在軟骨性內顱(cartilaginous neurocranium),而hif 3α會表現在咽弧(pharygeal arches)的部位。綜合上述我們推測hif 1α、 hif 3α對於頭部頭骨的發育扮演相當重要的角色,因此我們依據hif 1α、 hif 3α的 cDNA序列設計合成antisense反股之morpholino-integrated寡核酸(MO)(Heasman, 2002; Penberthy et al., 2002; Summerton and Weller, 1997),將這些寡核酸利用顯微注射(microinjection)送入斑馬魚胚胎當中,此寡核酸會與hif 1α、 hif 3α之mRNA配對進而抑制蛋白質的合成,之後注入hif 1α-MO、 hif 3α-MO的胚胎以頭骨發育相關專一的標視基因檢視,如:nkx2.3、shh、col2a1、gsc、hoxb2、fkd6、sox9a等,結果證明hif 1α、hif 3α對頭部頭骨發育扮演重要的角色。
Hypoxia-inducible factor 1 (HIF-1) is a master regulator of oxygen homeostasis that controls angiogenesis, erythropoiesis, and glycolysis via transcriptional activation of target genes under hypoxic conditions. HIF-1 is a heterodimeric complex, which is composed of a HIF-1α subunit and a HIF-1β/ARNT subunit, both of which are members of the basic helix-loop-helix (bHLH)-PAS family. Under hypoxia environment, the HIF-1 binds specifically to a 5’-RCGTG-3’ hypoxia-responsive element (HRE) in the promoter or enhancer of various hypoxia inducible genes, including erythropoietin, vascular endothelial growth factor, glucose transporters, and glycolytic enzymes, as well as genes involved in iron metabolism and cell survival.
Recently, two forms of hif-a cDNA, zhif-1α and zhif-3α, were cloned from zebrafish (Danio rerio) embryo. The spatiotemporal expression pattern of zhif-1α and zhif-3α in the embryo were analyzed by whole mount RNA in situ hybridization. Strong signal of zhif-1α and zhif-3α transcripts are detected in head sensory organs, otic plate, midbrain and hindbrain during development. To investigate the function of these genes in head development, zhif1a and zhif3a-specific morpholino-integrated antisense oligonucleotides (MO) were. It shows that zhif1α- and zhif3α- specific MO have severe effects in cranial skeleton development. Defective cranial skeleton development is comfirmed by the expression pattern changes of various cranial-specific markers, including nkx2.3, shh, col2a1, gsc. It suggests that zhif1α and zhif3α and their related signal pathway play important role in head skeleton development.
英文摘要………………………………………………………….1
中文摘要…………………………………………………………3
壹 、前言…………………………………………………………4
HIF蛋白背景介紹……………………………………………..4
HIF蛋白與胚胎發育…………………………………………6
HIF蛋白與腫瘤病理發生…………………………………….7
脊椎動物頭部發育……………………………………………7
斑馬魚頭骨發育………………………………………………9
貳、材料與方法……………………………………………………13
一. 材料…………………………………………………………13
A. 實驗生物……………………………………………….13
B. 菌種、質體……………………………………………..13
C. 一般化學藥品…………………………………………..13
D. 酵素及生化試劑…………………………………………13
E. 實驗藥品與配方………………………………………….14
二. 方法…………………………………………………………16
A. 斑馬魚飼養與受精胚胎之收集………………………..16
B. 斑馬魚組織全量核糖核酸RNA抽取………………….17
C. 核酸電泳分析…………………………………………...17
D. DNA分子之萃取 (DNA extraction)…………………...18
E. DNA重組接合 (Ligation)……………………………...19
F. 質體轉型 (Transformation)……………………………19
G. 反轉錄-聚合酵素連鎖反應(RT-PCR)………………....20
H. RNA全覆式原位雜交………………………………..21
I. 顯微注射 (Microinjection)……………………………….25
J. 骨頭染色( Alcian blue )………………………………….27
參、實驗結果………………………………………………………29
一、hif 1α, hif 3α morpholino(MO) 的注射…………………29
A. 外型胚胎之觀察………………………………………..29
B. 胚胎頭部軟骨型態的觀察……………………………..29
C . 胚胎頭骨大小之比較………………………………….30
二、利用hif 1α+hif 3α- MO對頭骨發育基因的影響……..30
A.內胚層細胞發育之標識基因的影響……………………..30
A-1.nkx2.3 ……………………………………………….30
A-2. fgf3………………………………………………….30
A-3.Shh…………………………………………………..31
A-4. foxa2……………………………………………….31
A-5.Gobbi……………………………………………….31
B. 中胚層細胞發之育標識基因…………………………32
B-1.Follistatin…………………………………………..32
B-2.col2a1………………………………………………32
B-3.Gsc…………………………………………………32
B-4.MyoD………………………………………………33
C. 後腦菱腦原節發育基因的影響………………………33
C-1. hoxa2………………………………………………33
C-2. krox20………………………………………………34
C-3. hoxb2……………………………………………….34
C-4. hoxb3……………………………………………….34
C-5. pax2.1………………………………………………35
D.調控神經塉遷移的基因之影響………………………….35
D-1. dhand﹙hand2﹚…………………………………..35
D-2. fkd6……………………………………………….36
D-3. dlx2………………………………………………36
D-4. dlx3 ………………………………………………37
E. 軟骨細胞分化基因……………………………………37
E-1.sox9a………………………………………………37
E-2.chm-1………………………………………………38
E-3.col2a1………………………………………………39
三.分別單一顯微注射 hif 1α- MO以及hif 3α- MO………39
A.外型觀察…………………………………………………40
B. 對頭骨發育相關基因的影響…………………………...40
B-1. krox20 ……………………………………………….40
B-2.dlx2 …………………………………………………40
B-3.Shh………………………………………………….41
B-4.nkx2.3……………………………………………….41
B-5.Gsc………………………………………………….41
貳、 討論…………………………………………………………42
參、 參考文獻…………………………………………………..47
肆、 附圖及照片……………………………………………….59
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