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At Single-Cell Resolution Characterising the molecular heterogeneity within human inhibitory interneurons – at single -cell resolution Francesca Keefe Thesis submitted for the degree of Doctor of Philosophy (PhD) Cardiff University, 4 -year Wellcome Trust funded PhD in Integrative Neuroscience September 2019 Acknowledgements Most importantly I would like to thank my primary supervisor, Meng Li, for her patience, encouragement and guidance over the past three years. There were occasions when either reassurance, space or gentle pushing were war ranted, and I truly appreciate Meng ’s help to see me through these times. Although there are many people I have had the joy to meet and work with during the last three years, there are a few who deserve mentioning by name. First, Zoe Noakes for all the tim e she spent in the early days train ing me in stem cell/ tissue culture work. There were certainly rocky times, but Zoe’s advice was always on point and greatly appreciated. Second, Adam Errington who provided me with training on whole -cell patch clamp tech nique and optogenetics. Adam’s will ingness to help and genuine interest in my optogenetics work made this element of my PhD possible in the short time span of my degree. Third, Sarah Edkins for her remarkable resource of knowledge concerning RNA sequencing . Sarah’s guidance when setting up my single -cell RNA sequencing work helped the study to successfully develop, and become a core part of my PhD. Finally, the Wellcome Trust funding has made this work and my time in Cardiff possible, and I will be forever thankful for this opportunity that has brought me to Cardiff and to all the new people that have become part of my life as a result. iii Abstract Inhibitory interneurons are a heterogeneous class of GABAergic neurons, classified into discrete subtypes b ased on the expression of molecular markers, physiology, morphology and connectivity. However, the mechanism of interneuron diversification is poorly understood. hPSC -derived interneurons may help solve the mystery, by providing an unrestricted trajectory of interneuron differentiation, which is not confounded by species differences. Although, how well the model recapitulates native development remains under scrutiny. Moreover, the full extent of interneuron subtype diversity that can be achieved in vitro i s unclear. Here an evaluation of hPSC model of interneuron differentiation has been presented. To tease apart the molecular heterogeneity, longitudi nal single - cell RNA sequencing was conducted. The analysis revealed a heterogeneous MGE -like enriched proge nitor population that differentiated into a diverse population of interneuron -like cells. On examining the authenticity of the model, using a novel c ross -comparison to the native human MGE (10WPC - 15WPC), encouraging similarities were found, especially betw een post -mitotic hPSC -derived interneurons and 15WPC MGE. However, several shortcomings of the model were also indicated. First, under -representation of specific genes encoding for transcription factors. Second, absent or low expression of late MGE markers and subtypes. Enforced expression of the under -expressed transcription factors may provide a means to enrich the interneuron -like population with th ese subtypes. Furthermore, the molecular resemblance to foetal -derived interneurons was reflected in the im mature intrinsic and evoked neuronal responses of hPSC - derived interneurons, recorded using whole -cell patch clamp. Nevertheless, monosynaptic viral tracing demonstrated the capability of the interneuron - like cells to make synaptic connections, which (alth ough not extensive) may be enhanced in a co -culture system. Overall, the interneuron differentiation of hPSC holds promise as a neurodevelopmental m odel. The novel characterisation of hPSC -derived interneurons and human MGE, at single -cell resolution, has simultaneously iv revealed the limitations and refinements necessary to generate more authentic and defined interneuron subtypes in vitro. Thereby, wid ening the scope and validity of the model. v Contents list DECLARATION ................................ ................................ ................... I ACKNOWLEDGEMENTS ................................ ................................ ... III ABSTRACT ................................ ................................ ...................... IV CONTENTS LIST ................................ ................................ ............. VI FIGURE LIST ................................ ................................ ............... XIII ABBREVIATION LIST ................................ ................................ ...... XV CHAPTE R 1 - GENE RAL INTRODUCTION ................................ ........... 1 1.1 Introduction ................................ ................................ ............... 1 1.2 Interneurons in pathology ................................ ......................... 1 1.3 Interneuron diversity ................................ ................................ 2 1.4 The region of origin ................................ ................................ .... 2 1.4.1 Spatial influence ................................ ................................ .... 3 1.4.1.1 Sonic hedgehog signalling ................................ .................. 5 1.4.1.2 WNT signalling ................................ ................................ .7 1.4.1.3 Retinoic acid signalling ................................ ....................... 8 1.4.2 Temporal influence ................................ ................................ .9 1.4.2.1 Early and late -born progenitors ................................ ........... 9 1.4.2.2 Cell cycle ................................ ................................ ....... 10 1.5 The region of destination ................................ ......................... 11 1.5.1 Tang ential migration ................................ ............................. 11 1.5.2 Circuit integration ................................ ................................ 11 1.5.3 Molecular and functional developmental trajectory ..................... 12 1.5.4 Region -dependent interneuron subtype composition .................. 14 1.5.5 Significance of extrin sic cues on lineage commitment ................. 15 1.6 Lineage commitment models ................................ ................... 16 1.7 Single -cell transcriptome analysis ................................ ........... 19 1.7.1 Principle ................................ ................................ ............. 19 1.7.2 Methodolog y................................ ................................ ........ 19 1.7.3 Applications ................................ ................................ ......... 22 1.8 The connectivity of neurons ................................ ..................... 23 vi 1.8.1 How to measure neuronal connectivity ................................ ..... 23 1.8.2 Principles of the monosynaptic rabies viral tracing system ........... 24 1.8.3 Applications ................................ ................................ ......... 25 1.9 Re search models ................................ ................................ ..... 29 1.9.1 Principles of neuron dif ferentiation of hPSC ............................... 29 1. 9.2 Interneuron differentiation of hPSC ................................ ......... 33 1.9.3 Application of hPSC -derived neuronal models ............................ 34 1.10 General aims ................................ ................................ .......... 34 CHAPTER 2 - MATERIAL AND METHODS ................................ ......... 36 2.1 Stem cell and tissue culture work ................................ ............ 36 2.1.1 General cell and primary tissue culture practice ......................... 36 2.1.2 Cell lines ................................ ................................ ............. 36 2.1.3 Cell maintenance for hESC lines ................................ .............. 36 2.1.4 Cell maintenance for HEK and BHK lines ................................ ... 37 2.1.5 Cell maintenance for human foetal tissue ................................ 38 2.1.6 Intern euron differentiation of hESC ................................ ......... 39 2.1.7 Sequential serial expansion of hESC -derived interneuron progenitors ................................ ................................ ................................ 41 2.2 Immunohistochemistry ................................ ............................ 42 2.3 Stages prior to quantitativ e polymerase chain reaction ........... 43 2.3.1 RNA extraction ................................ ................................ ..... 43 2.3.2 DNase treatment of RNA ................................ ........................ 44 2.3.3 Reverse transcription ................................ ............................ 44 2.4 Quantitative polym erase chain reaction ................................ .. 45 2.5 Molecular characterisation using single -cell RNA sequencing .. 45 2.5.1 Fluidigm C1 – single -cell capture and generation of single -cell cDNA ................................ ................................ ................................ 45 2.5.2 Quality control checks ................................ ........................... 46 2.5.2. 1 Bioanalyzer ................................ ................................ .... 46 2.5.2.2 Picogreen assay ................................ .............................. 47 2.5.2.3 Fluidigm Biomark - sin gle -cell QPCR ................................ ..
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