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Iron Homeostasis in Neuron-Glia Interaction

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Iron Homeostasis in Neuron-Glia Interaction Iron Homeostasis in Neuron-Glia Interaction Dissertation for the award of the degree Doctor rerum naturalium of the Georg-August University Göttingen within the program Genes and Development of the Georg-August University School of Science (GAUSS) submitted by Tina Kling born in Pforzheim, Germany Göttingen, 2016 Members of the Thesis Committee: Supervisor Prof. Dr. Mikael Simons Max Planck Institute for Experimental Medicine, Göttingen Department of Molecular Neurobiology, Technical University of Munich Second member of the thesis committee Prof. Dr. Christian Klämbt Institut für Neurobiologie, Westfälische Wilhelms Universität, Münster Third member of the thesis committee: Prof. Dr. Jörg Großhans Institut für Entwicklungsbiochemie, Universiätsmedizin, Göttingen Extended Thesis Committee: Prof. Dr. Gregor Bucher, Georg-August University Göttingen Prof. Dr. Ralf Heinrich, Georg-August University Göttingen PD Dr. Hauke Werner, Max Planck Institute for Experimental Medicine, Göttingen Date of Disputation: 19.09.2016 Affidavit I hereby declare that this PhD thesis “Iron Homeostasis in Neuron-Glia Interaction” has been written independently with no other aids or sources than quoted. Tina Kling July 2016 Göttingen, Germany All religions, arts and sciences are branches of the same tree. All these aspirations are directed toward ennobling man's life, lifting it from the sphere of mere physical existence and leading the individual towards freedom. Albert Einstein'Moral Decay', Out of My Later Years (1937, 1995) i Contents Contents .......................................................................................................................................... i List of Figures ............................................................................................................................ vi List of Tables ........................................................................................................................... viii Abbreviations ................................................................................................................................ ix Acknowledgements .................................................................................................................... xiii Summary ..................................................................................................................................... xiv 1 Introduction ............................................................................................................................ 1 1.1 Morphological classes of glia cells ................................................................................... 2 1.1.1 Origin and function of glia cells in the vertebrate system ...................................... 2 1.1.2 Glial cell types in Drosophila .................................................................................... 3 1.1.3 Layout of the larval nervous system of Drosophila ................................................. 5 1.1.4 Development of axonal ensheathment in the PNS ................................................. 6 1.1.5 Comparing axonal ensheathment between Vertebrates and Invertebrates ......... 8 1.2 Modes of neuron-glia interactions .................................................................................. 9 1.2.1 Signaling between neurons and glia ...................................................................... 10 1.2.2 Secreted molecules in the nervous system ........................................................... 10 1.2.3 Metabolic support in the nervous system of Vertebrates and Invertebrates ...... 12 1.3 Iron homeostasis ............................................................................................................ 13 1.3.1 Distribution and storage of iron ............................................................................ 13 1.3.2 Regulation of iron consumption ............................................................................ 15 1.3.3 Iron metabolism in the brain ................................................................................. 16 1.3.4 Iron homeostasis in Drosophila ............................................................................. 17 ii Contents 1.4 Aim of this work ............................................................................................................. 19 2 Material and Methods .......................................................................................................... 20 2.1 Buffer, Media and Solutions .......................................................................................... 20 2.2 Fly Genetics .................................................................................................................... 24 2.2.1 Maintenance and Crossing of Flies ........................................................................ 24 2.2.2 Germline transformation ....................................................................................... 24 2.2.3 Generation of recombinant fly lines ...................................................................... 24 2.2.4 Inhibitor Test of Ferroptosis inhibiting drugs ........................................................ 24 2.2.5 Isolation of primary cells from Drosophila Embryos ............................................. 25 2.2.6 List of fly lines ......................................................................................................... 26 2.3 Immunohistochemistry .................................................................................................. 29 2.3.1 Fixation and antibody staining of Drosophila primary cells .................................. 29 2.3.2 Dissection, fixation and antibody staining of larval nervous system .................... 29 2.3.3 Staining of iron in the larval tissue ........................................................................ 30 2.3.4 List of antibodies used for immunohistochemistry .............................................. 31 2.4 Molecular biology ........................................................................................................... 32 2.4.1 Bacteria strains ...................................................................................................... 32 2.4.2 Plasmids ................................................................................................................. 32 2.4.3 Transformation of DNA .......................................................................................... 33 2.4.4 DNA restriction ...................................................................................................... 33 2.4.5 Mini plasmid purification ....................................................................................... 33 2.4.6 Midi plasmid purification ....................................................................................... 34 2.4.7 Isolation of genomic DNA from tissue ................................................................... 34 2.4.8 Polymerase Chain Reaction ................................................................................... 34 2.4.9 Agarose gel electrophoresis .................................................................................. 35 2.4.10 Molecular Cloning .................................................................................................. 35 2.4.11 Sequencing and primer design .............................................................................. 35 Contents iii 2.5 Biochemical methods ..................................................................................................... 36 2.5.1 Protein extraction from Drosophila larvae ............................................................ 36 2.5.2 SDS polyacrylamide gel electrophoresis ................................................................ 36 2.5.3 Western blot and protein detection ..................................................................... 37 2.5.4 Cell type specific affinity isolation of translating Ribosomes (TRAP) .................... 37 2.5.5 DNAse treatment of RNA ....................................................................................... 39 2.6 Image acquisition, processing and equipment .............................................................. 39 2.6.1 Equipment used for image acquisition .................................................................. 39 2.6.2 Software ................................................................................................................. 40 2.6.3 Statistical analysis .................................................................................................. 41 3 Results ................................................................................................................................... 42 3.1 Screening of conserved glial proteins ............................................................................ 42 3.1.1 Selecting candidates that are necessary in vertebrates and invertebrates ......... 42 3.1.2 Screening concept and results .............................................................................. 42 3.2 p24-1 is crucial for the axon-glial architecture .............................................................. 44 3.2.1 p24-1 expression is essential for glial cells ............................................................ 44 3.2.2 p24-1 inhibition has an strong effect on axons ..................................................... 44 3.2.3 Weak glial defects after p24-1 inhibition in glial
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