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Studying BDNF Signalling Using Neurons Derived from Human Embryonic Stem Cells

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Studying BDNF Signalling Using Neurons Derived from Human Embryonic Stem Cells Studying BDNF signalling using neurons derived from human embryonic stem cells Spyridon Merkouris A thesis submitted to Cardiff University in accordance with the requirements for the degree of Doctor of Philosophy in the discipline of Neuroscience School of Biosciences, Cardiff University June 2020 1 DECLARATION This work has not been submitted in substance for any other degree or award at this or any other university or place of learning, nor is being submitted concurrently in candidature for any degree or other award. Signed ………………………………………… (candidate) Date ………………………… STATEMENT 1 This thesis is being submitted in partial fulfillment of the requirements for the degree of …………………………(insert MCh, MD, MPhil, PhD etc, as appropriate) Signed ………………………………………… (candidate) Date ………………………… STATEMENT 2 This thesis is the result of my own independent work/investigation, except where otherwise stated. Other sources are acknowledged by explicit references. The views expressed are my own. Signed ………………………………………… (candidate) Date ………………………… STATEMENT 4: PREVIOUSLY APPROVED BAR ON ACCESS I hereby give consent for my thesis, if accepted, to be available online in the University’s Open Access repository and for inter-library loans after expiry of a bar on access previously approved by the Academic Standards & Quality Committee. Signed ………………………………………… (candidate) Date ………………………… 2 “The energy of mind is the essence of life” Aristotle’s Metaphysics 12.1072b25 “ἡ γὰρ νοῦ ἐνέργεια ζωή” 3 ACKNOWLEDGEMENTS First and foremost, I would like to thank my supervisor, Yves Barde, for giving me the opportunity to work in his lab and providing his continuous guidance and advice throughout my PhD. His endless ideas and passion for science encouraged me when experiments did not work as expected. Thank you for your support and the exciting discussions during the last four years. Special thanks go to my co-supervisor Meng Li, who’s experience on human stem cells greatly facilitated my project. Meng and Claudia Tamburini introduced me to the techniques of human stem cell culture and for possibility to use equipment. Claudia was always there for scientific discussions, and the exchange of ideas made me more productive. I would like to extend my gratitude to Nick Allen whose experience on differentiating human stem cells offered me a very useful system to work with. I also wish to thank the whole Barde lab, but specific thanks go to Pedro Chacon Fernandez who always gave help when I needed it and for his advices; Hayley Dingsdale for giving me valuable feedback on this thesis; Xinsheng Nan for always being willing to share his great experimental expertise. Katharina, Laura, Sven, Jess and Natalia: thank you for the many enjoyable moments that we spent together, for the support and for the productive discussions. Thanks to all the members of the 3rd floor of the BIOSI 3 for creating an ideal working environment. Last, but not least I want to thank my friends and family for their reassurance and inspiration. I would like to thank in particular my parents for their love, continuous support and for always believing in me. Thank you, mam and dad, for everything that you have done for me. Special thanks also go to my sister Katerina for always being there when I needed her. I would also like to thank my good friend Giannis Kessidis for our long and stimulating discussions. 4 ABSTRACT As a result of a large number of in vitro as well as in vivo experiments with rodents, brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor TrkB are now widely appreciated to play major roles in brain function. There is also a growing appreciation that decreased BDNF signalling may be a significant component in a wide range of brain dysfunction in humans based on the discovery of mutations and polymorphisms in the corresponding genes. Yet still very little is known about BDNF expression and TrkB activation in human neurons or the human brain. In order to begin to address these questions, human embryonic stem cells (hESCs) have been used to generate large numbers of neurons suitable for biochemical experiments. In the work reported in the following chapters, two different protocols have been used to grow and differentiate hESCS. In the first, excitatory neurons were generated exhibiting detectable levels of BDNF albeit at low levels and after well over 2 months of culture. Detailed biochemical analyses that could significantly advance the field within a manageable time frame were also hampered by uncontrolled cell division still occurring in excitatory neurons even after extended culture periods. The use of a second, recently published differentiation protocol led to the significantly faster, more reproducible generation of large numbers of TrkB- expressing, mostly inhibitory neurons. A key feature of this robust differentiation protocol was the high proportion of BDNF-responsive cells allowing BDNF-induced phosphorylation to be studied with regard to time course and dose response. This system also allowed comparisons to be made between BDNF, the related factor neurotrophin-4 (NT4) and newly generated TrkB-activating antibodies. These TrkB-activating ligands were compared by extracting RNA from neurons treated for different time periods. One of the TrkB- activating antibody (designated #85) turned out to activate human TrkB at concentrations close to those of the natural ligands and with a strikingly similar pattern of induced mRNA transcripts, especially at early time points. The main conclusion of this work is that a test system based on the generation of BDNF-responsive neurons can be used to develop new reagents able to meaningfully activate TrkB. This work has been published in Merkouris et al 2018 in PNAS (https://www.pnas.org/content/115/30/E7023.long) 5 ABBREVIATIONS 7,8-DHF 7,8-Dihydroxyflavone Aβ Amyloid Beta ACAN Aggrecan ACKR3 Atypical Chemokine Receptor 3 AD Alzheimer’s Disease ADF Advanced DMEM F12 Akt see PKB AMPK 5’ Adenosine Monophosphate-Activated Protein Kinase AP-1 Activator Protein 1 Arc Activity-Regulated Cytoskeleton-Associated Protein ATF3 Activating Transcription Factor 3 BAD Bcl-2-associated Death Promotor Bcl-2 B-cell Lymphoma 2 BDNF Brain-Derived Neurotrophic Factor BDNF-AS BDNF Antisense bFGF Basic Fibroblast Growth Factor BMP Bone Morphogenetic protein BP Base Pairs BSA Bovine Serum Albumin BTG2 B-Cell Translocation Gene 2 CamKII Calcium/Calmodulin-Dependent Protein Kinase II cAMP Cyclic Adenosine Monophosphate 6 CaREs Calcium-Response Elements CaRF Calcium-Responsive Transcription Factor Cdk Cyclin-Dependent Kinase cDNA Complementary DNA CNS Central Nervous System CR Calretinin CRE cAMP Response Element CREB cAMP response element-binding protein CSRNP1 Cysteine and Serine Rich Nuclear Protein 1 Ct Cycle Threshold CTIP2 Chicken Ovalbumin Upstream Promotor Transcription Factor-Interacting Protein 2 CUX1 Cut Like Homeobox 1 CYR61 Cysteine Rich Angiogenic Inducer 61 DAPI 4’,6-diamidino-2 phenylindole DARPP-32 Dopamine- and cAMP-regulated neuronal phosphoprotein DIV Days in vitro DMAQ-B1 Demethylasterriquinone B-1 DMEM Dulbecco’s Modified Eagle Medium DMSO Dimethyl Sulfoxide DNA Deoxyribonucleic Acid dNTP Deoxynucleotide Triphosphates DTT Dithiothreitol DUSP1 Dual Specificity Phosphatase 1 EC50 Half Maximal Effective Concentration EDTA Ethylenediaminetetraacetic Acid EGF Epidermal Growth Factor 7 EGR Early Growth Reponse ERK Extracellular-Signal-Regulated Kinase ESC Embryonic Stem Cell ETV5 ETS Variant 5 FAM 6-carboxyfluorescein FAM83G Family With Sequence Similarity 83 Member G FCS Foetal Calf Serum FGF Fibroblast Growth Factor FOXP Forkhead Box Protein P FPKM Fragments Per Kilobase Million FRET Fluorescence Resonance Energy Transfer GABA Gamma-Aminobutyric Acid GAD Glutamate decarboxylase GEM Guanosine-5’-Triphosphate (GTP) Binding Protein Overexpressed in Skeletal Muscle GFAP Glial Fibrillary Acidic Protein GFR Growth Factor-Reduced GO Gene Ontology GPR G Protein-Coupled Receptor GSK3 Glycogen Synthase Kinase-3 GSX2 Genetic-Screened Homeobox 2 HAP1 Huntingtin Associated Protein 1 HD Huntington’s Disease HESCs Human Embryonic Stem Cells HIV Human Immunodeficiency Virus HRP Horseradish peroxidase HT High Throughput 8 Ig Immunoglobulin IPA Ingenuity Pathway Analysis iPSCs Induced Pluripotent Stem Cells JAK Janus Kinase kDa Kilodalton KLF Kruppel-like Factor LDS Lithium Dodecyl Sulphate LGE Lateral Ganglionic Eminence LIF Leukaemia Inhibitor Factor LOXHD1 Lipoxygenase Homology Domains 1 LRRTM1 Leucine Rich Repeat Transmembrane Neuronal 1 LTM Long-Term Memory LTP Long-Term Potentiation MAPK Mitogen-activated Protein Kinase MECP2 Methyl Cpg Binding Protein 2 MES 2-(N-Morpholino) Ethanesulfonic Acid MGB Minor Groove Binder MMP1 Matrix Metalloproteinase-1 mRNA Messenger RNA MSN Medium Spiny Neurons NAT Natural antisense transcript NF-κB Nuclear Factor Kappa B NGF Nerve Growth Factor NPAS4 Neuronal PAS Domain-Containing Protein 4 NR4A Nuclear Receptor Subfamily 4 Group A NT3 Neurotrophin-3 9 NT4 Neurotrophin-4 NTR Neurotrophin Receptor Oct-4 Octamer-Binding Transcription Factor 4 OLIG2 Oligodendrocyte transcription factor 2 PALD1 Phosphatase Domain Containing, Paladin 1 PAX6 Paired Box Protein 6 PC Principal Component PCA Principal Components Analysis PBS Phosphate Buffered Saline PBS-T Phosphate Buffered Saline, 0.1 % Triton X-100 PCR Polymerase Chain Reaction PD Parkinson’s Disease PDYN Prodynorphin PFA Paraformaldehyde PI3K Phosphoinositide 3-kinase PKB Protein kinase B (also Akt) PLCγ1 Phospholipase Cγ1 PMA Purmorphamine PMCH Pro-Melanin
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