ZEBRAFISH LIVER AND PANCREAS DEVELOPMENT: ROLES OF RBP4 IN EARLY LIVER FORMATION; GENETIC ABLATION TO DEDUCE PANCREAS CELL LINEAGE LI ZHEN NATIONAL UNIVERSITY OF SINGAPORE 2007 ZEBRAFISH LIVER AND PANCREAS DEVELOPMENT: ROLES OF RBP4 IN EARLY LIVER FORMATION; GENETIC ABLATION TO DEDUCE PANCREAS CELL LINEAGE LI ZHEN (B.Sc, Ocean University of China, China; M.Sc, Ocean University of China, China) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF BIOLOGICAL SCIENCES NATIONAL UNIVERSITY OF SINGAPORE 2007 Acknowledgements Acknowledgements I want to extend my greatest gratitude to my honorific supervisors: Prof Gong Zhiyuan (Department of Biological Sciences, NUS) and A/P Vladimir Korzh (Institute of Molecular and Cell Biology), for taking me as their student and appreciated their invaluable guidance and encouragement offered throughout my apprenticeship I also wish to give my heartfelt thanks to my PhD committee members, A/P Hong Yunhan (Department of Biological Sciences, NUS) and Assistant Prof Jiang Yunjin (Institute of Molecular and Cell Biology), for their helpful ideas and insights My research work has been done in both labs in Department of Biological Sciences, NUS and Institute of Molecular and Cell Biology I really appreciate the favors from all the friendly people: Cecilia, Hendrian, Hu Jing, Huiqing, Qingwei, Shizhen, Siew Hong, Tong Yan, Tuan Leng, Vivien, Weiling, Xiaoming, Xiao Ke, Xingjun, Xiufang, Yan Tie, Yilian, Zhengyuan, Zhiqiang from Dr Gong’s lab; and Ben, Catheleen, Dimitri, Gao Rong, Hang, Igor, Kar Lai, Lana, Lee Thean, Marta, Michael, Mike, Rayner, Sasha, Sergei, Shangwei, William, Zhanrui from Dr Korzh’s lab Special thanks to Steven Fong, for his painstaking proofreading and invaluable suggestions Also, I would like to thank people from the general office of DBS and the fish facility in the DBS and TLL/IMCB for their great assistants In addition, I would like to render my appreciation to National University of Singapore for providing me the graduate research scholarship during these years Finally, I dedicate this thesis to my dearest parents and family members: mother Tan Ruiqin, father, Li Xinyi, sister, Li Tao and husband Wang Tao whose love and care empowered me to pursue my dream and interest in research I Table of contents Acknowledgements Table of Contents Summary I II-V VI-VII List of Tables VIII List of Figures IX-X List of Common Abbreviations Publications Chapter I Introduction 1.1 Zebrafish embryonic development 1.2 Endoderm development 1.2.1 Gastrulation and early endoderm formation 1.2.2 Gut tube formation 1.3 Liver development 1.3.1 Liver progenitors 1.3.2 Signaling pathways in liver development 1.3.2.1 Liver competency and specification 1.3.2.2 Liver bud formation 1.3.2.3 Liver growth and differentiation 1.4 Pancreas development and cell lineage relationship 1.4.1 Exocrine pancreas 1.4.2 Endocrine pancreas 1.4.3 Signaling pathways and gene regulatory factors in pancreas development 1.4.3.1 Early pancreas specification 1.4.3.2 Pancreas bud formation 1.4.3.3 Pancreatic specification 1.4.3.4 Exocrine pancreas specification 1.4.3.5 Endocrine pancreas specification 1.4.4 Lineage analysis methodologies 1.4.5 Exocrine and endocrine pancreas cell lineage relationship 1.5 Rationale and objectives of the proposed study Chapter II Materials and Methods 2.1 DNA applications 2.1.1 DNA preparation and purification 2.1.1.1 Isolation and purification of plasmid DNA 2.1.1.2 cDNA synthesis 2.1.1.3 Recovery of DNA fragments from agarose gel 2.1.2 Recombinant DNA XI-XII XIII 6 10 11 11 12 13 14 15 16 17 17 18 19 20 21 22 23 25 27 28 28 28 29 29 29 II Table of contents 2.1.2.1 Restriction endonuclease digestion of DNA 2.1.2.2 DNA electrophoresis 2.1.2.3 Quantification of DNA by spectrophotometry 2.1.2.4 Ligation 2.1.2.5 Transformation 2.1.2.5.1 Preparation of competent cells 2.1.2.5.2 Transformation 2.1.2.6 Colony screening 2.1.3 Polymerase chain reaction (PCR) 2.1.3.1 Standard PCR 2.1.3.2 Reverse transcription PCR (RT-PCR) 2.1.3.3 Purification of PCR products 2.1.3.4 PCR product subcloning 2.1.4 DNA sequencing reaction 2.1.5 DNA vectors 2.1.5.1 pBluescript SK(+) 2.1.5.2 pGEM®-T Easy 2.1.5.3 pDrive 2.1.5.4 pEGFP-1 2.1.5.5 pDsRed-Express-1 2.1.5.6 DTA-mediated cell ablation 2.2 RNA applications 2.2.1 Isolation of total RNA 2.2.1.1 Isolation of total RNA from zebrafish embryos 2.2.1.2 Measurement of RNA concentration 2.2.1.3 RNA gel electrophoresis 2.3 Expression Analysis 2.3.1 Zebrafish 2.3.1.1 Fish maintenance 2.3.1.2 Mutant lines of zebrafish 2.3.2 Microinjection 2.3.2.1 Microinjection into 1-cell stage 2.3.2.2 Microinjection into YSL at hpf stage 2.3.3 Anti-sense morpholino design 2.3.4 Whole mount in situ hybridization on zebrafish embryos 2.3.4.1 Synthesis of labeled RNA probe 2.3.4.1.1 Linearization of plasmid DNA 2.3.4.1.2 Probe incubation and precipitation 2.3.4.1.3 Quantification of labeled probe 2.3.4.2 Preparation of zebrafish embryos 2.3.4.2.1 Embryo collection and fixation 2.3.4.2.2 Use of Anesthetic to View Embryos 2.3.4.2.3 Proteinase K treatment 2.3.4.2.4 Prehybridization 2.3.4.3 Hybridization 2.3.4.4 Post-Hybridization washes 2.3.4.5 Antibody incubation 2.3.4.5.1 Preparation of preabsorbed DIG 2.3.4.5.2 Incubation with preabsorbed antibodies 2.3.4.6 Color development 29 30 30 30 30 30 31 31 32 32 34 36 36 36 38 38 39 40 41 42 43 43 43 43 44 44 45 45 45 45 45 45 46 46 50 50 50 50 51 51 51 52 52 52 53 53 53 53 54 54 III Table of contents 2.3.4.7 Two-color whole mount in situ hybridization 2.3.5 Immunohistochemical staining 2.3.5.1 Primary antibody incubation 2.3.5.2 Secondary antibody incubation 2.3.5.3 Detection 2.3.6 Cryostat section 2.3.7 Double staining with mRNA probe and immunohistochemical staining 2.3.8 DAPI staining 2.3.9 Mounting and photography 2.3.10 Confocal microscopy and imaging of living embryos after anesthetizing 54 56 56 56 56 56 57 57 58 58 Chapter III Role of zebrafish retinol binding protein (rbp4) gene on early liver development 60 3.1 Spatial and temporal expression of rbp4 gene during embryogenesis 3.1.1 Sequence analyses of rbp4 cDNA 3.1.2 Temporal expression of rbp4 gene from fertilization onwards 3.1.3 Spatial expression of rbp4 gene 3.2 Regulation of rbp4 gene expression 3.2.1 rbp4 gene expression pattern in YSL changed in mutants belonging to nodal and hh signaling pathway 3.2.2 RA positively regulates rbp4 expression in YSL 3.3 Knockdown of rbp4 gene results in change of yolk shape and double liver formation 3.3.1Yolk and yolk extension shape changed in rbp4 gene knockdown 3.3.2 Two liver buds formed at both left and right side in rbp4 gene knockdown 3.3.3 Exocrine pancreas, endocrine pancreas and heart remain normal after rbp4 knockdown 3.4 Discussion 62 62 63 63 67 67 68 70 70 76 83 85 Chapter IV Isolation of somatostatin2 (sst2) and glucagona (gcga) promoters and generation of gfp transgenic zebrafish 93 4.1 Isolation of zebrafish sst2 gene promoter and establishment of stable GFP transgenic line under the sst2 promoter 4.1.1 Sequence analysis of zerafish sst2 promoter 4.1.2 Specific activation of gfp reporter gene in endocrine pancreas and floor plate cells under the 2,467-bp zebrafish sst2 promoter 4.1.3 Generation and characterization of stable Tg(sst2:gfp) lines 4.1.4 GFP expression in adult Tg(sst2:gfp) 4.2 Isolation and characterization of zebrafish and fugu gcg promoters 4.2.1 zebrafish gcga promoter 4.2.2 Fugu gcga promoter 4.3 Discussion 4.3.1 sst2 promoter analysis 4.3.2 Generation of stable Tg(sst2:gfp) line and analysis of pancreas development 4.3.3 gcga promoter analysis 96 96 103 108 113 116 116 119 121 121 122 125 IV Table of contents Chapter V Analysis of zebrafish exocrine and endocrine pancreas lineage 128 5.1 Ablation of the exocrine pancreas 5.1.1 Specific ablation of exocrine pancreas by transient expression of DTA under the elaA promoter 5.1.2 Endocrine cells are not affected by pElaA-DTA ablation 5.2 Ablation of ins expressing β-cells 5.2.1 Specific ablation of ins expressing β-cells by transient expression of DTA under the ins promoter 5.2.2 Analysis of recovery of β-cells in pINS-DTA affected embryos 5.2.3 Effect of β-cell ablation on α- and δ-cells 5.3 Ablation of sst2 expressing δ-cells 5.3.1 Specific ablation of δ-cells by transient expression of DTA under the sst2 promoter 5.3.2 Analysis of recovery of δ-cells in δ-cell ablation 5.3.3 Effect of δ-cell ablation on β- and α-cell 5.3.3.1 Effect of δ-cell ablation on β-cells 5.3.3.2 Effect of δ-cell ablation on α-cells 5.4 Effects of endocrine pancreatic cell ablation on development of exocrine pancreas, liver and intestine 5.5 A tentative model of zebrafish endocrine pancreas cell lineage relationship 130 130 References 134 138 138 142 146 150 150 154 157 157 160 165 167 170 V Summary SUMMARY Liver and pancreas are endoderm organs possessing both endocrine and exocrine functions Although their development has been intensively studies in mammals, the knowledge on liver progenitors and pancreas cell lineage remains poor As such, the zebrafish, a promising model for development study, has been used in this study to investigate the two aspects To investigate the early liver development, expression and function of a gene encoding retinol binding protein (Rbp4), a plasma transporter of retinol, was analyzed rbp4 was expressed in the ventro-lateral yolk syncytial layer (YSL) at 12-16 hpf and later expanded to cover the posterior YSL We demonstrated that rbp4 expression was negatively regulated by Nodal and Hedgehog (Hh) signalling and positively controlled by retinoic acid Knockdown of Rbp4 in the YSL resulted in shortened yolk extension as well as the formation of two liver buds, which could be due to impaired migration of liver progenitor cells Rbp4 appeared also to regulate the gene encoding the extracellular matrix protein Fibronectin1 (Fn1) specifically in the ventro-lateral yolk, indicating a role of fn1 in liver progenitor migration Since exocrine pancreas, endocrine pancreas, intestine and heart developed normally in Rbp4 morphants, we suggest that rbp4 expression in the YSL is required only for early liver development, especially for migration of liver progenitors To study the pancreas cell lineage relationship, we firstly isolated and characterized the zebrafish somatostatin (sst2) and glucagon a (gcga) promoters Using the zebrafish sst2 promoter, we successfully generated three GFP transgenic lines that faithfully recapitulated sst2 expression in the endocrine pancreas Secondly, we employed diphtheria toxin gene A chain (DTA) mediated cell ablation method to eliminate either exocrine pancreas (elaA expressing cells) or endocrine pancreas (ins VI Summary or sst2 expressing cells) It turned out that endocrine pancreas and exocrine pancreas are independent of each other during development Among endocrine pancreas, we showed that ablation of the β-cells resulted in more profound defects in α-cells and almost no defects in δ-cells, while ablation of δ-cells resulted in reduction both in αand β-cells In addition, we showed that ablations of either exocrine pancreas cells or endocrine pancreas (β- and δ-) cells have no obvious effect on development of other endodermal organs such as the liver and intestine In conclusion, this study explored two aspects of endoderm development in zebrafish By investigation of rbp4 gene, we showed that YSL expressing rbp4 has specific function in early liver development especially in migration of liver progenitors, indicating a role of retinol in early liver development By study of pancreas cell lineage in zebrafish, we suggested that while morphogenesis of pancreas is largely evolutionary conserved, minor difference in the cell lineage relationship of endocrine cells may exist between fish and mammals VII List of tables List of Tables Table 2-1 Primers Used in Standard PCR 33 Table 2-2 Primers Used in RT-PCR 35 Table 2-3 A List of 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28 28 28 29 29 29 II Table of contents 2 .1. 2 .1 Restriction endonuclease digestion of DNA 2 .1. 2. 2 DNA... analysis of pancreas development 4.3.3 gcga promoter analysis 96 96 10 3 10 8 11 3 11 6 11 6 11 9 12 1 12 1 12 2 12 5 IV Table of contents Chapter V Analysis of zebrafish exocrine and endocrine pancreas lineage. .. electrophoresis 2 .1. 2. 3 Quantification of DNA by spectrophotometry 2 .1. 2. 4 Ligation 2 .1. 2. 5 Transformation 2 .1. 2. 5 .1 Preparation of competent cells 2 .1. 2. 5 .2 Transformation 2 .1. 2. 6 Colony screening 2 .1. 3