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Neurogenesis in the Enteric Nervous System

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IN VIVO IDENTIFICATION OF NEURAL STEM CELLS IN THE ENTERIC NERVOUS SYSTEM Cátia Susana Torres Laranjeira January, 2010 Division of Molecular Neurobiology MRC National Institute for Medical Research The Ridgeway Mill Hill, London NW7 1AA Department of Cell and Developmental Biology University College London Thesis submitted to University College London for the degree of Doctor of Philosophy ACKNOWLEDGEMENTS “The journey, not the arrival, matters” (T.S. Elliot) At (almost) the end of this journey it is time to acknowledge all those that, one way or another, made it so memorable. I am very grateful to Vassilis for all his support and guidance throughout my PhD. His unrelenting patience, passion for science and enthusiasm has been a major inspiration. To the members of the Vassilis Lab, past and present, I would also like to extend my deepest gratitude. In particular, I wish to thank Katarina for her invaluable help with the surgical procedures and Reena for sharing with me all her knowledge about ES cells, molecular biology, etc. Also, a big thank you to Dipa, Reena and Valentina (note the alphabetical order!!!): you kept my feet on the ground when I was getting too high and propped me up when I found the going tough. For your daily support, encouragement, understanding and, most of all, for your friendship, I cannot thank you enough. I would also like to thank all the members of the Molecular Neurobiology division for making such a friendly working environment and for the stimulating feedback on our divisional meetings. I wish to thank Nicoleta Kessaris and Matthew Grist for their generous help, advice and reagents. I am very grateful to Iain Robinson and Elke Ober for all their useful advice and interesting scientific discussions. Also, a big thank you to Eileen for her kind help and good will. Finally, this work was funded by Fundação para a Ciência e Tecnologia and I am grateful for their funding during my PhD. 2 Acknowledgements This thesis is dedicated to my dear family. Dad and Mum, words cannot express everything you mean to me. Your boundless faith and unconditional love are the foundation of my existence. Ana, my beloved sister, your strength, determination and generosity have inspired me no end. You are and always will be my favorite person in the world. My brother-in-law Pedro, for sharing with us all the joys and sorrows of this crazy close-knit family. And Joao, my partner and best friend, without your love, tender encouragement and reassuring confidence I would have not made it this far. Thank you all for being there for me. 3 DECLARATION OF AUTHENTICITY I, Cátia S. T. Laranjeira declare that all the work presented in this thesis is the result of my own independent investigation. Where information has been derived from other sources, I confirm that this has been indicated and cited accordingly. This work has not been previously submitted as part of any other degree course or to another university. Catia Laranjeira January, 2010 4 ABSTRACT The enteric nervous system (ENS) in vertebrates is derived from neural crest cells which emerge during embryogenesis from the hindbrain and, following stereotypical migratory pathways, colonize the entire gastrointestinal tract. Assembly of enteric ganglia and formation of functional neuronal circuits throughout the gut depends on the highly regulated differentiation of enteric neural crest stem cells (eNCSCs) into a plethora of neuronal subtypes and glia. The identification of eNCSCs and the lineages they generate is fundamental to understand ENS organogenesis. However, the study of the properties of eNCSCs has been hindered by the lack of specific markers and genetic tools to efficiently identify and follow these cells in vivo. Although previous in vitro studies have suggested that Sox10-expressing cells of the mammalian gut generate both enteric neurons and glia, the differentiation potential of these Sox10+ cells in vivo is currently unclear. Here, we have developed a genetic marking system which allows us to identify Sox10+ cells and follow their fate in vivo. Using this system we demonstrate that Sox10+ cells of the gut generate both enteric neurons and glia in vivo, thus representing multilineage ENS progenitors. To examine whether the neurogenic potential of Sox10+ eNCSCs is temporally regulated over the course of gut organogenesis, we generated additional transgenic mouse lines expressing a tamoxifen-inducible Cre recombinase (iCreERT2) under the control of the Sox10 locus (Sox10iCreERT2). Activation of iCreERT2 in Sox10iCreERT2 transgenic mice at specific developmental stages and analysis of enteric ganglia from adult animals showed that the pool of Sox10+ cells progressively lose their neurogenic potential. 5 Abstract These findings raise the question of the origin of multilineage ENS progenitors isolated from cultures of post-neurogenic gut. By combining genetic fate mapping in mice, cultures of enteric ganglia and an ENS injury model, we demonstrate that glial cells in the adult ENS retain neurogenic potential which can be activated both in vitro and in vivo, in response to injury. The signals that lead Sox10+ progenitor cells to become either neurons or glial cells remain unclear. We hypothesized that the receptor tyrosine kinase RET may be part of the molecular fate switch between the two lineages being able to divert differentiation of eNCSCs away from the glial lineage and towards the neuronal fate. Here, we describe a genetic strategy to attain persistent expression of RET in vivo, in a temporally and spatially controlled manner. Such a strategy will allow us to assess the role of RET in ENS differentiation during development. Taken together, our data provide a framework for exploring the molecular mechanisms that control enteric neurogenesis in vivo and identify glial cells as a potential target for cell replacement therapies in cases associated with congenital absence or acquired loss of enteric neurons. 6 TABLE OF CONTENTS Acknowledgements.......................................................................................2 Declaration of Authenticity...........................................................................4 Abstract……………......................................................................................5 Table of Contents...........................................................................................7 List of Figures and Tables...........................................................................12 Abbreviations……………………………………………………………...14 Chapter I – General Introduction………………………………………17 1.1 Enteric Nervous System: structure, organization and function……………..18 1.1.1 Structure and organization of the ENS…………………………………18 1.1.2 Functions of the ENS………………………………………………...19 1.1.3 Characteristics of the ENS……………………………………………20 1.2 Enteric Nervous System: origin and development…………………………21 1.2.1 Embryonic origin of the ENS…………………………………………21 1.2.2 Development of the ENS……………………………………………..24 1.3 Cellular and Molecular mechanisms of ENS differentiation………………..26 1.3.1 Molecular control of the generation and maintenance of the ENS progenitor pool……………………………………………………………………..27 1.3.2 Molecular regulation of enteric neuronal differentiation………………....35 1.3.3 Molecular control of enteric glia differentiation…………………………39 1.4 Lineages of the enteric nervous system……………………………………41 1.4.1 Phenotype of NC-derived cells that form the ENS………………………41 1.4.2 Enteric neuronal cells………………………………………………...43 1.4.3 Enteric glial cells…………………………………………………….46 1.4.4 Enteric neural stem cells……………………………………………...53 7 Table of Contents 1.5 Neurogenesis in the enteric nervous system……………………………….60 1.5.1 Neurogenesis in the embryonic and postnatal ENS……………………...60 1.5.2 Neurogenesis in the adult ENS………………………………………..62 1.5.3 Changes in enteric neurons with aging…………………………………66 1.6 Diseases of the enteric nervous system…………………………………….67 1.6.1 Hirschsprung’s disease and other congenital enteric neuropathies………...67 1.6.2 Other ENS disorders…………………………………………………71 1.6.3 Transplantation models………………………………………………72 1.7 Aims of this thesis………………………………………………………..74 Chapter II – Materials and Methods…………………………………...76 2.1 General material and equipment…………….………………………...…77 2.1.1.General chemicals, buffers and solutions……………………………….77 2.1.2.Centrifuges………………………………………………………….77 2.1.3.Polymerase Chain Reaction (PCR) machines…………..…………….…78 2.1.4.Other equipment…………………………………………………….78 2.2.Generation of the Sox10iCreERT2 construct and transgenic mice…………..78 2.2.1.Generation of the targeting vector……………………………………..78 2.2.2.Phage Artificial Chromosome (PAC) isolation and modification………….80 2.2.3.Generation of Sox10iCreERT2 transgenics……………………………...80 2.3.Generation of R26RET9 and R26RET9(MEN2A) constructs and transgenic mice…..81 2.3.1.Construction of the transgenes………………………………………...81 2.3.2.Generation of transgenic mice………………………………………...82 2.4.Generation of Sox10Cre; R26ReYFP……………………………………..83 2.5.Generation of hGFAPCreERT2; R26ReYFP………………………………83 2.6.Molecular Techniques……………………………………………………………83 2.6.1.Genomic DNA Isolation……………………………………………..83 8 Table of Contents 2.6.2.Plasmid DNA isolation………………………………………………84 2.6.3.Analysis of DNA……………………………………………………85 2.6.4.Bacterial Strain, growth and storage…………………………………...87 2.6.5.Colony lifts…………………………………………………………88 2.6.6.Cloning techniques…………………………………………………..88 2.6.7.PAC techniques……………………………………………………..90 2.6.8.Polymerase Chain Reaction (PCR) analysis……………………………94 2.6.9.Riboprobe synthesis………………………………………………….97 2.7.Tissue Manipulation
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