WNT SIGNALING IN THE EARLY DEVELOPMENT OF ZEBRAFISH SWIMBLADDER AND XENOPUS LUNG YIN AO NATIONAL UNIVERSITY OF SINGAPORE 2011 WNT SIGNALING IN THE EARLY DEVELOPMENT OF ZEBRAFISH SWIMBLADDER AND XENOPUS LUNG YIN AO B.Sc, Huazhong Agricultural University (HZAU), China M.Sc, Huazhong Agriculural University (HZAU), China A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF BIOLOGICAL SCIENCES NATIONAL UNIVERSITY OF SINGAPORE 2011 Acknowledgements Acknowledgements I want to extend my greatest gratitude to my supervisors: Prof. Zhiyuan Gong (Department of Biological Sciences, NUS) and A/P Vladimir Korzh (Institute of Molecular and Cell Biology), for taking me into the PhD program and for their invaluable guidance and encouragement through all these years. I also wish to give my thanks to my PhD committee members, Dr. Karuna Sampath (Tamasek Lifesciences Laboratory, TLL), A/P Winkler Christoph and A/P Yih-Cherng Liou (Department of Biological Sciences, NUS) for their insightful suggestions. I conducted my research work in both labs in Department of Biological Sciences, NUS and Institute of Molecular and Cell Biology. I want to thank the favors from all the lab mates: Ahn Tuan, Caixia, Choong Yong, Grace, Hendrian, Huiqing, Lili, Li Zhen, Sahar, Siew Hong, Ti Weng, Tina, Vivien, Yan Tie, Zhengyuan, Zhou Li from Dr Gong’s lab; and Catheleen, Dimitri, Hang, Hong Yuan, Igor, Jun Yan, Kar Lai, Melven, Siau Lin, Shu Lan, Steven, William from Dr Korzh’s lab. Special thanks go to Dr. Cecilia Lanny Winata and Dr. Svetlana Korzh for their warmhearted helps and painstaking proofreading of manuscripts as well as invaluable suggestions. In addition, I would like to thank people from the general office of DBS and the fish facility in the DBS and IMCB, and the Xenopus facility from IMCB and Dr. Micheal Jones’ lab for their great assistants. In addition, I would like to thank Ministry of Education and National University of Singapore for providing me the graduate research scholarship. Finally, I am indebted to my dearest parents and family members: father, Yin Baiquan, mother, Sun Xiuzhen, wife, Dr. Wu Jingming and daughter Yin Qian Ying Gracie, whose love and care empowered me to pursue my PhD degree. I Table of contents Acknowledgements I Table of Contents II VIII Summary List of Tables X XI XII XIII XIV List of Figures List of Common Abbreviations Publications XV Chapter I. Introduction 1.1 Evolutionary link between the lung and the swimbladder 1.2 The evolution history of fishes 1.3The evolution of teleost swimbladder 1.4Development of the mammalian lung 1.4.1 Morphogenesis of the lung 1.4.2 Molecular control of lung development 1.5 Xenopus lung development 1.6 Zebrafish as a model system 1.6.1 Zebrafish as an experimental model 1.6.2 Position of zebrafish in the taxonomy of fishes 1.6.3 The zebrafish genome 1.6.4 Zebrafish in developmental biology research 1.6.4.1 Endoderm Development in zebrafish 1.6.4.1.1 Specification of early endodermal progenitors in the zebrafish embryo 1.6.4.1.2 Formation of the gut tube 1.6.5 Development of the zebrafish swimbladder 1.7 The Wnt signaling 1.7.1 The discovery of Wnt signaling 1.7.2 The Wnt gene family 1.7.3 Classification of Wnt signaling and Wnts 1.7.4 Mechanism of Wnt signaling II 7 10 12 13 13 14 14 15 16 17 18 19 20 20 21 22 23 Table of contents 1.7.5 Wnt proteins 1.7.6 Wnt receptors 1.7.7 Non-Wnt agonists of β-catenin/Tcf signaling 1.7.8 Wnt antagonists and inhibitors 1.7.9 Wnt target genes 1.7.10 Wnt signaling in lung and lung development 1.7.11 Wnt signaling in Xenopus lung development 1.7.12 Wnt signaling in Zebrafish 1.8 Objectives of the 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 2.1.1.3 Recovery of DNA fragments from agarose gel 2.1.2 Recombinant DNA 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 Quantitative real-time PCR 2.1.3.4 Purification of PCR products 2.1.3.5 PCR product sub-cloning 2.1.4 DNA sequencing reaction 2.1.5 DNA vectors 2.1.5.1 pGEM®-T Easy 2.1.5.2 pEGFP-1 2.2 RNA applications 2.2.1 Isolation of total RNA III 26 27 28 29 29 31 32 33 33 36 37 37 37 38 38 38 38 39 39 39 39 40 40 41 41 41 44 45 45 45 46 46 47 48 48 Table of contents 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 2.2.1.4 cDNA synthesis 2.3 Expression Analysis 2.3.1 Zebrafish 2.3.1.1 Fish maintenance 2.3.1.2 Mutant and transgenic lines of zebrafish 2.3.1.3 Heat-shock treatment of zebrafish transgenic embryos 2.3.1.4 Treatment of zebrafish embryos with the small molecule IWR-1 2.3.2 Microinjection 2.3.3 Anti-sense morpholino design 2.3.4 Whole mount in situ hybridization (WISH) 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 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 IV 48 49 50 50 50 50 50 51 51 52 52 53 54 54 54 55 55 56 56 56 56 57 57 58 58 58 58 59 59 59 60 60 60 61 61 61 Table of contents 2.3.10 Confocal microscopy and imaging of living embryos 2.3.11 Whole mount in situ hybridization (WISH) on Xenopus embryos Chapter III. Wnt signaling in early Xenopus lung development 3.1 Screening for lung-specific genes in X. troplicalis and activation of their promoters in X. laevis and zebrafish 3.1.1 Screening of lung-specific genes in Xenopus troplicalis 3.1.2 Activation of Xenopus tropicalis sftpc promoter in Xenopus laevis and zebrafish 3.2 Expression of components of Wnt and Hedgehog pathways in different tissue layers during early lung development in Xenopus laevis 3.2.1 Early Xenopus lung morphogenesis based on sftpc and nkx2.1 expression 3.2.2 Expression of wnt7b in the epithelium of early Xenopus lung 3.2.3 Expression of wnt5a and wif1 in the mesenchyme of Xenopus lung 3.2.4 Examination of shh and bhh expression in Xenopus lung 3.2.5 Expression of acta2 and anxa5 in early Xenopus lung 3.3 Discussion 3.3.1 Xenopus as a model for developmental study 3.3.2 Gene expression in developing lungs in Xenopus 62 63 65 66 67 70 72 72 76 76 80 80 84 84 85 Chapter IV. Wnt signaling in the early development of the zebrafish swimbladder 89 4.1 Identification of a new set of gene markers for different tissue layers of the zebrafish swimbladder 4.2 Expression of Wnt pathway members in the swimbladder during early development 4.2.1 Screening of Wnt signaling genes expressed in the swimbladder 4.2.2 Expression of Wnt ligands in early developing swimbladder 4.2.3 Expression of Wnt receptors in swimbladder 4.2.4 Expression of Wnt transcription factors in the swimbladder 4.2.5 Expression of Wnt signaling target genes in the swimbladder 4.2.6 Expression of Wnt protein inhibitor gene wif1 in early developing swimbladder 4.3 Conditional Blocking of Wnt signaling by heat-shock reveals its critical roles in early swimbladder development 4.3.1 Inhibition of Wnt signaling by heat-shock of hs:Dkk1-GFP and hs:∆TcfGFP transgenic embryos 4.3.2 Stage-specific inhibition of Wnt signaling impaired swimbladder development in the epithelium 91 V 94 94 96 101 101 101 102 107 107 110 Table of contents 4.3.3 Blocking of Wnt signaling perturbed mesenchyme development and smooth muscle differentiation 4.3.4 Blocking of Wnt signaling disturbed the outer mesothelium development 4.3.5 Wnt signaling was required for cell proliferation 4.3.6 Wnt signaling was required for the inhibition of apoptosis 4.4 Inhibition of Wnt signaling by small molecule chemical IWR-1 4.4.1 Dosage dependent effects of IWR-1 on swimbladder specification 4.4.2 Timing-dependence of IWR-1 treatment for swimbladder specification and growth 113 115 117 117 121 121 121 4.4.3 IWR-1 treatment affected budding of the second swimbladder chamber 4.4.4 IWR-1 treatment affected development of all three tissue layers 4.4.5 IWR-1 treatment did not alter the expression level of sox2 and wif1 in swimbladder 4.5 Functional analysis of Wnt ligands in the early swimbladder development 4.5.1 wnt5b was required for the normal development of the swimbladder 4.5.2 Knockdown of wnt11 alone did not disturb the early swimbladder development 4.5.3 wnt5b and wnt11 might play redundant roles in the specification of mesenchyme cells in the swimbladder 122 123 123 4.5.4 wnt1 knockdown perturbed the programs in all three tissue layers in the swimbladder 4.6 Up-regulation of Wnt signaling by Knockdown of Wnt inhibitor gene wif1 affected the early swimbladder development in zebrafish 4.6.1 Knockdown of wif1 expression by antisense morpholinos 4.6.2 Morpholino validation by p53 dependence analysis and mRNA rescue 4.6.3 wif1 morpholino knockdown affected early development of swimbladder 4.6.4 wif1 morpholinos knockdown disturbed the development of epithelium, mesenchyme, mesothelium and smooth muscle differentiation 4.7 Crosstalk between Wnt and Hh signaling in the swimbladder development 4.7.1 Wnt signaling maintained Hh signaling and is negatively regulated by Hh signaling 4.7.2 Hh signaling might be required to maintain wif1 expression 133 4.8 Crosstalk between Wnt signaling and tbx2a signaling regulated the early swimbladder development 4.8.1 Expression of tbx2a in the early developing swimbladder 4.8.2 tbx2a knockdown mimicked the effects of Wnt signaling suppression in the development of the three tissue layers of the swimbladder 4.8.3 Expression of Tbx2a target gene cx43 in the early swimbladder 4.8.4 Wnt signaling repressed tbx2a expression but enhanced cx43 expression in the swimbladder 4.8.5 Wnt signaling but not wif1 was negatively regulated by tbx2a VI 129 129 129 129 135 135 137 137 140 142 142 142 146 146 146 147 151 151 Table of contents 4.9 Discussion 4.9.1 The conserved and non-conserved expression patterns of genes suggested the conservation and deviation of the fish swimbladder and tetrapod lung 154 154 4.9.2 The genetic strategies for the study of swimbladder development 157 4.9.3 Timing of swimbladder specification and morphogenesis among endoderm organs 4.9.4 Differential efficiency and impacts of blocking Wnt signaling in the two conditional Wnt signaling suppression transgenic lines on swimbladder development 4.9.5 Wnt signaling is required for formation of the anterior chamber bud of the swimbladder 4.9.6 Crosstalk among different tissue layers during the early swimbladder development 4.9.7 Crosstalk of Wnt signaling with Hh signaling and Tbx signaling 4.9.8 Differentiation of mesenchymal cells at early stages and their effects on epithelial cell growth 4.9.9 Possible roles of Wnt2 in the second swimbladder chamber budding 4.9.10 Dosage dependent Wnt signaling for swimbladder development 158 4.10 Conclusions References VII 159 160 161 162 164 164 165 166 172 Summary Summary Comparative study of lung and swimbladder development is not only an important issue in developmental biology, but also an attractive topic in evolutionary biology. However, although the homology between lung and swimbladder is supported by their common morphological origin and blood supply from the 6th branchial artery, molecular evidence remains largely missing. Previously, we demonstrated that many genes important for induction of lung bud and early lung development are also expressed in zebrafish swimbladder development. In particular, Hedgehog signaling pathway, essential for lung development, is also required for proper development of all the three tissue layers of the swimbladder. Although the Wnt signaling pathway has been reported to play a critical role in mammalian lung development, the role of Wnt signaling in zebrafish swimbladder and Xenopus lung development has not been investigated. In the current study, we investigated Wnt signaling in the Xenopus and zebrafish models. The expression of sftpc, nkx2.1, wnt7b, wnt5a, wif1 and shh in different tissue layers of early Xenopus lung were demonstrated. 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Expression of Wnt receptors and transcription factors in the swimbladder 100 Expression of axin1 and axin2 in the early development of zebrafish swimbladder Expression of wif1 in the early developing swimbladder Induction of GFP-fusion proteins and inhibition of Wnt signaling in the hs:Dkk1-GFP and hs:∆Tcf-GFP transgenic embryos by heat-shock treatment Effects of temporal inhibition of wnt signaling on the. .. Test of the X tropicalis sftpc promoter in X laevis and zebrafish Expression of sftpc (spC) in early lung development of Xenopus laevis 71 74 Fig.3-4 Expression of Nkx2.1 in early development of Xenopus lung epithelium 75 Fig.3-5 Expression of wnt7 b in the lung epithelium 78 Fig.3-6 Expression of wnt5 a and wif1 in the mesenchyme of Xenopus lung 79 Fig.3-7 Expression of shh and bhh in early Xenopus lung. ..Summary Furthermore, we investigated the roles of Wnt ligand genes wnt1 , wnt5 b and wnt1 1 in the early development of the zebrafish swimbladder and revealed the synergetic roles of wnt5 b and wnt1 1 for the specification of mesenchymal cells in swimbladder More importantly, we demonstrate that Wnt signaling is required for the budding of a second swimbladder bud Proper development of swimbladder requires... 131 Fig 4-22 Design and validation of wif1 morpholinos 136 Fig 4-23 Validation and rescue of wif1 morpholinos 139 Fig 4-24 Effects of wif1 morpholino knockdown on the development of three tissue layers of the swimbladder Crosstalk of Wnt and Hh signaling in swimbladder development 141 Requirement of Hh signaling for wif1 expression Expression of tbx2a in the early development of the swimbladder 145 149... mimics inhibition of Wnt signaling in early swimbladder development Expression of cx43 in the early development of the swimbladder Fig 4-30 Wnt signaling inhibited tbx2a expression but promoted cx43 expression 152 Fig 4-31 tbx2a negatively regulated Wnt but not wif1 expression Schematic depiction of crosstalk between Wnt, Hh and Tbx2a signaling 153 Schematic representation of Wnt signaling requirement in. .. swimbladder requires a proper level of Wnt signals In addition, the cross-talks between Wnt signaling and Hedgehog signaling as well as tbx2a signaling were investigated In conclusion, our study demonstrates that the roles of Wnt signaling are conserved between the early development of the zebrafish swimbladder and tetrapod lung IX List of tables List of Tables Table 2-1 Primers Used in X tropicalis promoter... I and type II), which line the inner surface of the developing lung and trachea The three distinct layers of the mammalian lung have been well characterized histoligically (Hogan, 1999) The lung is the main respiratory organ in terrestrial vertebrates Air goes through the respiratory tract, which includes the nasal cavity, pharynx, and trachea; and finally travels into the bronchi and bronchioles into... early Xenopus lung development 82 Fig.3-8 Expression of acta2 and anxa5 in early Xenopus lung development 83 Fig 4-1 94 Fig 4-2 Fig 4-1 Expression of new maker genes in different tissue layers of the zebrafish swimbladder as assayed by WISH Expression of wnt5 b and wnt1 1 in the early developmental swimbladder Fig 4-3 Examination of wnt2 expression pattern 99 Fig 4-4 Detailed examination of wnt2 expression... signaling on the epithelium development of swimbladder Effects of temporal inhibition of Wnt signaling on swimbladder mesenchyme and smooth muscles Effects of temporal inhibition of Wnt signaling on swimbladder mesothelium development 105 Fig 4-5 Fig 4-6 Fig 4-7 Fig 4-8 Fig 4-9 Fig 4-10 Fig.4-11 98 104 106 110 112 114 116 Fig 4-12 Effects of Wnt inhibition on cell proliferation in the swimbladder 119 Fig... 4-13 Effects of Wnt inhibition on cell apoptosis in the swimbladder Design and validation of wif1 morpholinos Dosage-dependent effect of IWR1 on specification of swimbladder epithelial cells 120 Fig 4-14 XI 124 List of figures Fig 4-15 Timing of requirement of Wnt signaling for swimbladder specification and growth Dosage-dependent effect of IWR-1 treatment on the formation of the second swimbladder . WNT SIGNALING IN THE EARLY DEVELOPMENT OF ZEBRAFISH SWIMBLADDER AND XENOPUS LUNG YIN AO NATIONAL UNIVERSITY OF SINGAPORE 2011 WNT SIGNALING IN THE EARLY DEVELOPMENT. 18 1.6.5 Development of the zebrafish swimbladder 19 1.7 The Wnt signaling 20 1.7.1 The discovery of Wnt signaling 20 1.7.2 The Wnt gene family 21 1.7.3 Classification of Wnt signaling and Wnts 22 1.7.4. target genes 29 1.7.10 Wnt signaling in lung and lung development 31 1.7.11 Wnt signaling in Xenopus lung development 32 1.7.12 Wnt signaling in Zebrafish 33 1.8 Objectives of the study 33 Chapter