斑馬魚胚胎six3基因表現調控機制之探討: 內中胚層基因調控網路six3b的角色暨six3a表現在前腦及眼之調控

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研究生：	趙崇豪 Chao, Chung-Hao
論文名稱：	斑馬魚胚胎six3基因表現調控機制之探討: 內中胚層基因調控網路six3b的角色暨six3a表現在前腦及眼之調控 Explore the regulatory mechanisms of six3 genes in zebrafish embryos : The role of six3b in mesendoderm gene regulatory networks and the regulation of six3a during forebrain and eye development
指導教授：	汪宏達 Wang, Horng-Dar 喻秋華 Yuh, Chiou-Hwa
口試委員:	藍忠昱胡清華黃聲蘋
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 生物科技研究所 Biotechnology
論文出版年：	2011
畢業學年度：	99
語文別：	中文
論文頁數：	143
中文關鍵詞：	斑馬魚、內中胚層、基因網路調控、眼睛、前腦
外文關鍵詞：	zebrafish, mesendoderm, gene regulatory networks, eye, forebrain
相關次數：	點閱：3 下載：0
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Six3基因屬於Six/Sine oculis基因家族中的一員。有六種Six家族的基因在不同的物種中被發現，其中Six3和Six6對於脊椎動物的前腦和眼睛發育相當重要。本論文旨在利用模式生物斑馬魚，研究six3b基因參與的基因調控網路，以及研究six3a基因表現的調控機制。首先，我先介紹Six基因家族以及過去對於Six3在生物發育上的研究，也提及Six3基因異常造成的人類疾病。其次我研究基因調控網路特別著重於six3b。利用嗎啉基反義寡核苷酸抑制斑馬魚Six3b的表現，並以及時定量聚合酶鏈反應尋找會受Six3b影響的下游基因。我發現在百分之五十外包期，six3b會增加otx1之表現，並降低mybbp1a之表現。在百分之七十五外包期，six3b會提高mybbp1a、foxh1、otx2之表現，並減少etv5之表現。在體分節期six3b調控許多神經外胚層的轉錄因子，這些轉錄因子已知和腦部不同區域的特化有關。我也發現了gbx1、gbx2、otx2會減少six3a以及six3b的表現，形成回饋循環。接下來我進一步研究six3a表現的調控機制。six3a上游兩個演化保守區域A和D對six3a具有重要的調控作用：在早期D增強six3a大量表現，晚期A促進six3a表現於視網膜以及前腦最前端、D誘導six3a表現在整個眼睛、腦和軀幹、A可抑制six3a在軀幹的表現。由缺失突變及A和D的點位突變，我找到了數個可能的轉錄因子結合位置可能與其作用有關，也用電泳遷移實驗證實胚胎之核萃取物含有可結合其上之蛋白質。接下來我進一步尋找誘導six3a在早期表現的增強子D上之結合蛋白。藉由增強子D內的高度保留序列當做探針，我們發現在斑馬魚six3b的上游存在與six3a增強子D序列相似，並功能類似的序列。比對兩者序列後我發現其中含有一個高度保留的同源箱(homebox)蛋白結合位置TAATTA，此發現意味著這段序列可能扮演重要的角色。我藉由試管內和活體內的實驗方法測試三種同源箱蛋白Boz, Gsc,以及Otx2結合上此位的可能性。實驗結果發現Otx2可能結合上此位置，並誘導斑馬魚six3的起始表現。

Table of Contents                    I
List of Figures and Tables           IV
中文摘要                             VI
Abstract                             VII

Chapter 1 Introduction
1 Overall introduction                  1
2 Mesoderm Gene Regulatory Networks     1
3 Complexity of cis-regulatory organization of six3a  5
4 Transcription factors for six3 early expression     7
5 The Six gene family                                 10
6 Function of Six3 for embryonic development          11
7 Human diseases related to SIX3 mutation             11
8 The role of Six3 in gene regulatory network         16

Chapter 2 Materials and Methods
1 Zebrafish husbandry, experimentation and care/welfare 20
2 Morpholino injections                                 20
3 RNA extraction and real time RT-PCR                   20
4 Establish gene regulatory network using BioTapestry   22
5 DNA constructs and site-directed mutagenesis          22
6 Microinjection and microscopic photography            23
7 Electrophoresis mobility shift assay (EMSA)           23
8 Cell culture and transfection                         25
9 Protein extraction and Western blot                   25
10 Chromatin immunoprecipitation                        26

Chapter 3 The gene regulatory subcircuit center by six3b
1 Results                                               27
1.1 Gene expression profile of six3a and six3b in zebrafish development                                     28
1.2 Phenotypic defects of six3a and six3b morphants     29
1.3 The six3b downstream genes at early stages          29
1.4 The six3b downstream targets at later stage on neuroectoderm                                             29
1.5 Upstream inputs of six3b and six3a                 30
1.6 Construction of six3b subcircuits                  31
2 Discussion
2.1 The role of six3 in mesoderm                       32
2.2 The role of six3 for neuroectoderm                 32

Chapter 4 Transcription regulation of six3a in zebrafish
1 Results                                       39
1.1 Identification of the cis-regulatory modules for six3a expression                                         39
1.2 Brn3 and Pax6.1 binding sites on modules B and C contain no enhancer function in the forebrain or eyes up to 24 hpf                                                   40
1.3 Identification of modules D and A, together with the basal promoter, as early enhancers                       42
1.4 Deletion analysis of module A identified several activator binding sites                                  43
1.5 Deletion analysis in module D elucidated multiple activator binding elements                               46
1.6 Silencer function of module A for the suppression of the ectopic expression of module D                       48
1.7 EMSA for modules D and A                           48
2 Discussion
2.1 Two evolutionarily conserved modules and many minimal functional elements work together to achieve correct six3a expression                                               51
2.2 POU domain transcription factor is important for activating six3a expression                              53
2.3 Pax6a binds to six3a module A to activate expression in the eye and brain                                     53
2.4 Other possible transcription factors regulating six3a expression                                               54

Chapter 5 The transcription factor responsible for early expression of module D
1 Results                                              94
1.1 Both zebrafish six3a and six3b have D module while module A is not found in six3b                           94
1.2 The D module also plays an enhancer role to regulate both six3a and six3b express from early stage            95
1.3 The last 28 bp in module D plays a role in regulating six3a expression at 6 hpf                                96
1.4 Two zebrafish homeobox genes gsc and boz did not function at six3a D module by in vitro assays            97
1.5 Otx2 functions at six3a D module may through the homeobox protein binding site in the last 28 bp of six3a module D                                                 99
2 Discussion
2.1 The finding of D module in zebrafish and other vertebrates                                              101
2.2 Boz and Gsc may regulate six3 through other cis-elements or through indirect mechanism                   102
2.3 The role of six3 activation by Otx2                103
2.4 Other methods to know the transcription regulation of six3                                                     104
Conclusion and perspective                               118
References                                               121
Appendixes
Appendix 1. Sequence of morpholinos                      133
Appendix 2. The sequences of the Q-PCR primers of the candidate genes                                          134
Appendix 3. The sequences of the primers for the candidate genes used for in situ hybridization                     135
Appendix 4. Expression profiles of 35 transcription factor                                                   136
Appendix 5. Downstream target genes of sox17, sox32, foxa2, gata6, gata5, otx2, six3b, gbx2, and gbx1                137
Appendix 6. Upstream inputs for foxa2, gata6, gata5, otx2, six3a, six3b, sox32, sox17, gbx2, and gbx1               139
Appendix 7. The gene regulatory networks control the developmental process at five different stages           141
Publications                                           143
Oral presentations, posters and workshops                144

                                

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