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Molecular and Cellular Dissection of Zebrafish Larvae Tail Regeneration

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Molecular and Cellular Dissection of Zebrafish Larvae Tail Regeneration Molecular and Cellular Dissection of Zebrafish Larvae Tail Regeneration PhD thesis by Maria Montserrat Garcia Romero The Bateson Centre Department of Biomedical Science University of Sheffield February 2016 Abstract Regeneration is the ability of organisms to restore their structures in form and function. While it is present in the complete animal kingdom, humans retain the capacity to restore some tissues and organs, but this capacity is limited in comparison with that of other vertebrates such as the zebrafish. Further, the growth of regenerative diseases and the lack of therapies to fully restore damaged organs and limbs highlight the importance of the study of regeneration. To further the understanding of the regeneration process, this study focuses on molecular and cellular dissection of the tail regeneration of zebrafish larvae. The molecular dissection found that the molecular signalling Hedgehog regulates re- generation through the Wnt and Fibroblast Growth Factor (FGF) developmental pathways as follows. The regeneration marker genes msxc, dlx5a and raldh2 are regulated by Hedgehog (Hh) through Wnt signalling, while cell proliferation is reg- ulated by Hh through FGF signalling. Further, the role of Hh during regeneration is unique and different to its role during normal tail development, where it is not essential. Finally, it was found that the muscle differentiation marker myod is ex- pressed sequentially after the regeneration marker genes raldh2 and dlx5a during the late stage of tail restoration. For the cellular dissection cell lineage tracings during regeneration were per- formed using several Cre expressing lines with tissue specific promoters, where Cre recombination is controlled by 4OH Tamoxifen administration. The lineage trac- ing analysis showed that both blood vessels and periderm cells participate during tail restoration and that both cell types remain lineage committed. Altogether the results presented in this thesis show that the zebrafish larva tail is a suitable model to study both molecular and cellular aspects of regeneration. The knowledge generated during this PhD research can contribute to set the basis for the development of clinical therapies to assist human regeneration. Acknowledgement I would like to thank my supervisor Dr. Henry Roehl for the opportunity to work in his lab for the duration of my PhD. I want to express my gratitude for all the support and advice provided during both my Master’s and PhD, but mainly during the first months that were very challenging for me. I really appreciate all the motivation given and the trust to develop my research. This PhD research would not have been possible without the help of the aquar- ium staff, I would like to thank the manager of the aquarium Claire Allen for her advice regarding fish handling. I would like to thank my lab mates and friends that were beside me during the my PhD. I want to say big thank you to my husband Tillmann for all the support provided during the difficult moments of the PhD and the advice about my thesis writing. I want to thank the Mexican society for being always there during the difficult times of being far away from home. I want to thank my sponsor CONACyT for giving me the opportunity to make my post-grad research in Sheffield University. I would like to thank my parents America Romero and Pedro Garcia for being so supportive and being a big example of personal improvement as well as my siblings Fabiola Garcia and David Garcia. And finally I would like to thank all the wonderful people that I meet during this personal journey that makes my experience richer and more interesting. II Contents 1 General Introduction 1 1.1 Regeneration . 1 1.1.1 Types of regeneration . 2 1.1.2 Animal models where regeneration is present . 3 1.1.3 The zebrafish as a model for the study of regeneration . 5 1.1.4 Structures of zebrafish that can regenerate and their mech- anisms. 6 1.1.5 The use of zebrafish larvae to study tail regeneration. 7 1.2 Molecular mechanisms involved during zebrafish tail regeneration . 7 1.2.1 Importance of FGF signalling during the initiation of tail regeneration and proliferation . 8 1.2.2 Importance of Wnt/β-catenin signalling and RA during the blastema creation. 9 1.2.3 Hh is necessary for bone ray patterning. 10 1.2.4 Regeneration marker genes expressed during tail regenera- tion . 10 1.3 Molecular mechanisms involved during zebrafish tail development . 11 1.3.1 Pathways expressed during tail bud formation . 11 1.3.2 The importance of Hh, FGF, and Wnt signalling during tail formation . 11 1.4 Cellular mechanisms involved during zebrafish tail regeneration . 12 1.4.1 Formation of wound epidermis and blastema . 12 1.4.2 Dedifferentiation and transdifferentiation mechanisms . 13 1.4.3 Cell proliferation and tail outgrowth . 13 1.5 Lineage tracing methods . 14 1.5.1 Direct observation and cell labelling with dyes . 14 1.5.2 Genetic markers . 15 1.5.3 Cell and tissue transplantation . 16 III IV CONTENTS 1.6 Cre-lox as a tool to track cell lineages during tail regeneration . 16 1.6.1 Description of Cre -lox system . 17 1.6.2 Zainbow multilox system . 17 1.6.3 Previous studies using the Cre-lox system during tail regen- eration . 20 1.6.4 Models to be tested with the use of Cre-lox system. 22 1.7 Aims and objectives . 22 2 Material and Methods 26 2.1 Zebrafish husbandry . 26 2.2 Tail amputation, regeneration and chemical treatment . 26 2.2.1 Fin fold amputation and regeneration . 27 2.2.2 Chemical treatment . 27 2.3 Whole mount in-situ hybridization and regeneration marker detection 29 2.4 Evaluation of gene expression . 32 2.5 Whole mount antibody staining . 33 2.6 Heat Shocks transgenic lines . 34 2.7 16 Somite (S) and 1dpf embryo collection and molecular pathway analysis . 37 2.8 raldh2 expression analysis in the tail bud, under the suppression of FGF signalling and overexpression of Wnt signalling. 37 2.9 Quantification of the total are of raldh2 staining in the tail bud . 38 2.10 Mounting and image capture . 39 2.11 Restriction digestion DNA . 41 2.12 DNA electrophoresis, gel cutting and DNA gel extraction . 41 2.13 DNA dephosphorylation, ligation and subcloning . 42 2.14 Bacterial transformation . 42 2.15 DNA amplification and extraction by plasmid preparation . 43 2.16 Creation of the cryaa Venus ...................... 44 2.17 Synthesis of the Cre-expressing construct with the use of Gateway kit 44 2.18 Assessment of the genetic incorporation of the construct by DNA injection in one-cell stage embryos . 49 CONTENTS V 2.19 Screening of transgenic zebrafish by identification positive founders (F0) ................................... 49 2.20 Raising of the transgenic progeny of positive F1 and F2 founders into adulthood . 50 2.21 Double transgenic fish husbandry by crossing the Cre expressing fish with the Lox expressing line . 50 2.22 4OH tamoxifen administration in the double transgenic fish and live imaging of the tissue recombination . 50 2.23 Selection of embryos that present tissue recombination in the tail and live imaging during tail regeneration . 51 2.24 Double antibody staining for mCherry and Phospho histone H3 . 51 3 Dissection of the pathways involved during zebrafish tail regen- eration. 52 3.1 Introduction . 52 3.2 Hh signalling plays an important role at the beginning of tail regen- eration . 55 3.2.1 The zebrafish larval tail possesses regenerative capabilities . 55 3.2.2 Hedgehog signalling as an early activator during zebrafish tail regeneration . 57 3.2.2.1 Hedgehog expression at early time points during tail regeneration . 59 3.2.3 Hedgehog signalling is not dependent upon Wnt, FGF or RA pathways during tail regeneration . 61 3.2.4 Fin fold and tail regeneration are regulated in a different manner by Hh signalling . 62 3.3 Wnt signalling is downstream of Hedgehog during zebrafish tail re- generation . 65 3.3.1 Wnt signalling is able to regulate regeneration marker genes in a more direct way than Hedgehog signalling . 65 3.3.1.1 Wnt signalling is expressed at a later time point than Hh signalling during tail regeneration . 65 3.3.2 Hh signalling is required for Wnt activation during tail re- generation . 67 3.3.3 Wnt signalling is epistatic of Hh signalling during the ex- pression of regeneration marker genes . 70 3.4 FGF signalling is downstream of Hh and Wnt signalling during ze- brafish tail regeneration . 70 VI CONTENTS 3.4.1 FGF signalling readouts are down regulated under a contin- uous suppression of Hh signalling during tail regeneration . 70 3.4.2 Wnt signalling regulates FGF readouts during zebrafish tail regeneration . 72 3.4.3 FGF signalling is epistatic to Hh signalling during cell pro- liferation in zebrafish tail regeneration . 73 3.4.4 raldh2 signalling down-regulation by SU5402 cannot be res- cued by Wnt signalling up-regulation during tail regeneration 77 3.5 Discussion . 79 3.5.1 Hh signalling is upstream of Wnt signalling during larva ze- brafish tail regeneration. 80 3.5.2 Hedgehog and Wnt regulates some FGF markers in both indirect and direct fashion . 81 3.5.3 Cell proliferation was rescued once fgf3 was up-regulated . 82 3.5.4 FGF signalling affects raldh2 expression during tail regener- ation in a more direct way than Wnt. 82 3.6 Conclusions . 83 4 Dissection of the pathways involved during zebrafish tail devel- opment. 85 4.1 Introduction . 85 4.2 Molecular dissection during zebrafish tail development. 86 4.2.1 Hedgehog has a crucial role during tail regeneration that is not observed during tail development.
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