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GATA Transcription Factors and Their Co-Regulators Guide the Development Of GATA transcription factors and their co-regulators guide the development of GABAergic and serotonergic neurons in the anterior brainstem Laura Tikker Molecular and Integrative Biosciences Research Programme Faculty of Biological and Environmental Sciences Doctoral Programme Integrative Life Science University of Helsinki ACADEMIC DISSERTATION Doctoral thesis, to be presented for public examination, with the permission of the Faculty of Biological and Environmental Sciences of the University of Helsinki, in Raisio Hall (LS B2) in Forest Sciences building, Latokartanonkaari 7, Helsinki, on the 3rd of April, 2020 at 12 noon. Supervisor Professor Juha Partanen University of Helsinki (Finland) Thesis Committee members Docent Mikko Airavaara University of Helsinki (Finland) Professor Timo Otonkoski University of Helsinki (Finland) Pre-examinators Docent Satu Kuure University of Helsinki (Finland) Research Scientist Siew-Lan Ang, PhD The Francis Crick Institute (United Kingdom) Opponent Research Scientist Johan Holmberg, PhD Karolinska Institutet (Sweden) Custos Professor Juha Partanen University of Helsinki (Finland) The Faculty of Biological and Environmental Sciences, University of Helsinki, uses the Urkund system for plagiarism recognition to examine all doctoral dissertations. ISBN: 978-951-51-5930-4 (paperback) ISBN: 978-951-51-5931-1 (PDF) ISSN: 2342-3161 (paperback) ISSN: 2342-317X (PDF) Printing house: Painosalama Oy Printing location: Turku, Finland Printed on: 03.2020 Cover artwork: Serotonergic neurons in adult dorsal raphe (mouse). Sert in situ hybridization with DAPI staining. An original image by Laura Tikker. Table of Contents List of original publications Abbreviations ABSTRACT 1. INTRODUCTION ............................................................................................................................................. 1 2. LITERATURE REVIEW ................................................................................................................................. 2 2.1. GATA TFs and their co-regulators .......................................................................................................... 2 2.1.1. GATA TFs ........................................................................................................................................ 2 2.1.1.1. Functions and mechanisms of GATAs in cell differentiation: haematopoiesis as a paradigm...... 3 2.1.2. TAL1 and TAL2 ............................................................................................................................... 5 2.1.3. ZFPM1 and ZFPM2 .......................................................................................................................... 6 2.2. Determination of neuronal cell fate and diversity in the central nervous system ................................ 8 2.2.1. Early development of the central nervous system: formation of the neural tube .............................. 9 2.2.2. Patterning of the neural tube ........................................................................................................... 10 2.2.2.1. Anterior-posterior patterning....................................................................................................... 10 2.2.2.2. Dorsal-ventral patterning............................................................................................................. 12 2.2.3. Determination of cell fate ............................................................................................................... 14 2.2.3.1. Proneural genes control neurogenesis and cell fate ..................................................................... 14 2.2.3.2. Post-mitotic cell fate determination by selector genes ................................................................ 15 2.3. Function of GATA TFs in the development of GABAergic and serotonergic neurons ..................... 16 2.3.1. GATA TFs and their co-regulators in the central nervous system .................................................. 16 2.3.2. GABAergic neurons ....................................................................................................................... 16 2.3.2.1. Development of GABAergic neurons ......................................................................................... 17 2.3.2.2. GABAergic nuclei in the anterior brainstem ............................................................................... 19 2.3.3. Serotonergic neurons ...................................................................................................................... 22 2.3.3.1. Development of serotonergic neurons ......................................................................................... 22 2.3.3.2. Dorsal raphe ................................................................................................................................ 24 3. AIMS OF THE STUDY .................................................................................................................................. 27 4. MATERIALS AND METHODS .................................................................................................................... 28 5. RESULTS AND DISCUSSION ...................................................................................................................... 31 5.1. Analysis of progenitor domains, heterogeneity of ventral r1, and characterization of nuclei derived from ventral r1 (I-III) ................................................................................................................................... 31 5.2. GATA TFs and their co-regulators TAL1 and ZFPM2 regulate the development of GABAergic neurons in r1 (I, III) .......................................................................................................................................... 37 5.3. GATA2, GATA3 and ZFPM1 control different aspects of serotonergic neuron development in r1 (II, IV) ............................................................................................................................................................. 39 6. CONCLUDING REMARKS .......................................................................................................................... 48 Acknowledgements.............................................................................................................................................. 50 References ............................................................................................................................................................ 51 List of original publications The current thesis is based on two original articles and two manuscripts which will be referred to as Roman numerals (I-IV) in the text. The articles I and II are printed by permission from Development. I. Lahti L., Haugas M., Tikker L., Airavaara M., Voutilainen M.H., Anttila J., Kumar S., Inkinen C., Salminen M., Partanen J. (2016) Differentiation and molecular heterogeneity of inhibitory and excitatory neurons associated with midbrain dopaminergic nuclei. Development. Feb 1;143(3):516-29. II. Haugas M.*, Tikker L.*, Achim K., Salminen M., Partanen J. (2016) Gata2 and Gata3 regulate the differentiation of serotonergic and glutamatergic neuron subtypes of the dorsal raphe. Development. Dec 1;143(23):4495-4508. III. Morello F.*, Borshagovski D.*, Survila M.*, Tikker L.*, Kirjavainen A., Estartús N., Knaapi L., Lahti L., Mazutis L., Delogu A., Salminen S., Partanen J. Molecular fingerprint and developmental regulation of the tegmental GABAergic and glutamatergic neurons derived from the anterior hindbrain. Submitted. IV. Tikker L., Casarotto P., Biojone C., Piepponen P., Estartús N., Seelbach A., Laukkanen L., Castrén E., Partanen J. Inactivation of the GATA cofactor ZFPM1 results in abnormal development of dorsal raphe serotonergic neuron subtypes and increased anxiety-like behaviour. Submitted. *these authors contributed equally to the work Contributions: Study I: L.T. performed the chicken in ovo electroporation experiments, participated in the mouse gene expression studies, analysed the data and made a major contribution to the preparation of figures. Study II: L.T. participated in the experimental design and analysis of the serotonergic neuron subtype markers. L.T. conducted the experiments with the Cre-reporter mouse lines, neuronal birth-dating, and Gata3CKO as well as Gata2CKO;Gata3CKO mouse mutants. L.T. made a major contribution to the analysis of the data, preparation of the figures, and writing of the manuscript. Study III: L.T. carried out the experiments involving VTg and DTg development, Zfpm2CKO and Sox14GFP mouse mutants and birth-dating. L.T. made a major contribution to the validation of the scRNAseq results, analysis of the data, preparation of figures and writing of the manuscript. Study IV: L.T. participated in the experimental design and conducted most of the experiments including Zfpm1 expression studies and analysis of Zfpm1CKO and Zfpm1CKO;Zfpm2CKO mutant mice. L.T. was involved in the studies of Zfpm1CKO mouse behaviour. L.T. analysed the data, prepared all the figures and wrote the first draft of the manuscript. Abbreviations 5-HT 5-hydroxytryptamine, serotonin bHLH basic helix-loop-helix protein family CLP common lymphoid progenitor CMP common myeloid progenitor CNS central nervous system DR dorsal raphe DRD dorsal part of dorsal raphe DRVL ventrolateral part of dorsal raphe DTg dorsal tegmental nucleus E embryonic day GMP granulocyte/macrophage progenitor
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