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Microglial Migration and Adhesion Molecules During Embryonic Brain Development Sophie Smolders

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Microglial Migration and Adhesion Molecules During Embryonic Brain Development Sophie Smolders Microglial migration and adhesion molecules during embryonic brain development Sophie Smolders To cite this version: Sophie Smolders. Microglial migration and adhesion molecules during embryonic brain development. Neurons and Cognition [q-bio.NC]. Université Pierre et Marie Curie - Paris VI; Universiteit Hasselt (1970-..), 2017. English. NNT : 2017PA066533. tel-01890177 HAL Id: tel-01890177 https://tel.archives-ouvertes.fr/tel-01890177 Submitted on 8 Oct 2018 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Université Pierre et Marie Curie Universiteit Hasselt CERVEAU - COGNITION - COMPORTEMENT Neurosciences Paris Seine, UPMC INSERM S 1130, CNRS UMR 8246 Development of Spinal Cord Organization La migration des microglies et les molécules adhésives au cours du développement embryonnaire du cerveau Par Sophie Smolders Thèse de doctorat de Neurosciences Dirigée par Pascal Legendre et Bert Brône Présentée et soutenue publiquement le 30 octobre 2017 Devant un jury composé de : Prof. dr Marcel Ameloot, Universiteit Hasselt, Diepenbeek, Belgium, Maître de conférences Prof. dr. Bert Brône, Universiteit Hasselt, Diepenbeek, Belgium, promotor Dr. Pascal Legendre, Université Pierre et Marie Curie, Paris, France, promotor Prof. dr. Niels Hellings, Universiteit Hasselt, Diepenbeek, Belgium Dr. Isabelle Dusart, Université Pierre et Marie Curie, Paris, France Dr. Michel Mallat, Université Pierre et Marie Curie, Paris, France Dr. Etienne Audinat, Université Paris Descartes, Paris, France, rappoteur Prof. Dr. Charles ffrench-Constant, University of Edinburgh, Edinburgh, UK, rapporteur “What we observe is not nature itself, but nature exposed to our method of questioning” Werner Heisenberg Microglia. Río-Hortega, 1919 & 1921 Table of contents Table of contents I List of Abbreviations V CHAPTER 1: 1 General introduction and aims 1.1 Basics of embryonic brain development 3 1.1.1 Progenitor amplification: E9-E12 3 1.1.2 Neurogenesis and cortical layering: E11-E18 4 1.1.3 Angiogenesis: from E8.0 4 1.1.4 Gliogenesis: E16-P20 5 1.2 The microglial cell: versatile outsider and one of a kind 6 1.2.1 Origin of microglia 7 1.2.2 Migration into the CNS 9 1.2.3 Microglial maturation inside the CNS 15 1.2.4 Homeostasis of microglia in the adult CNS 16 1.2.5 Undersigned, I, the microglial cell 17 1.2.6 Parenchymal and non-parenchymal CNS macrophages 18 1.2.7 Physiological functions of microglia 22 1.2.8 Functions of microglia in pathology 26 1.2.9 Gender differences 30 1.3 Cell Migration 31 1.3.1 ECM 32 1.3.2 Integrins 35 1.3.3 ECM/integrin signaling in microglia and their mobility 39 1.4 Study aims 42 CHAPTER 2: 45 Complex invasion pattern of the cerebral cortex by microglial cells during development of the mouse embryo 2.1 Abstract 46 2.2 Introduction 46 2.3 Materials and methods 47 2.4 Results 50 2.5 Discussion 62 I CHAPTER 3: 65 Age-specific function of α5β1 integrin in microglial migration during early colonization of the developing mouse cortex 3.1 Abstract 66 3.2 Introduction 66 3.3 Materials and Methods 67 3.4 Results 72 3.5 Discussion 87 CHAPTER 4: 95 The CXCL12/CXCR4/integrinß1 signaling axis in microglial migration: an exploratory study 4.1 Abstract 96 4.2 Introduction 96 4.3 Materials and Methods 98 4.4 Results 102 4.5 Discussion 114 4.6 Conclusion 119 4.7 Supplemental data description 119 CHAPTER 5: 129 Maternal immune activation evoked by polyinosinic:polycytidylic acid does not evoke microglial cell activation in the embryo 5.1 Abstract 130 5.2 Introduction 130 5.3 Materials and Methods 132 5.4 Results 134 5.5 Discussion 145 CHAPTER 6: 149 General discussion and perspectives 6.1 Properties of microglia during colonization of the embryonic brain 150 6.1.1 Morphology and protein markers 151 6.1.2 Maturation and the microenvironment 152 6.2 The microglial migration behaviour in the embryonic brain 152 6.2.1 Microglial settlement during embryogenesis 153 6.2.2 Regulation of microglial migration speed 154 6.3 Complex regulation of integrin function in microglial migration during development 155 6.4 Candidate cues for steering parenchymal microglial migration during development 156 II 6.4.1 Chemoattractants and chemorepellants 156 6.4.2 Cell death and synaptogenesis 157 6.5 Microglial interactions with blood vessels 158 6.5.1 Mechanisms of interaction 158 6.5.2 Attraction towards blood vessels 158 6.5.3 Mechanisms of influencing blood vessel branching 159 6.6 Does microglial activation by maternal immune activation lead to neurodevelopmental disorders? 160 6.6.1 Priming of microglia 160 6.6.2 Reported alterations in microglia upon MIA 161 6.6.3 Controversies in microglial activation following MIA 161 6.7 Limitations of this work 162 6.8 Outstanding questions 164 List of references 165 Résumé 189 Nederlandse samenvatting 191 English summary 193 Curriculum Vitae 195 Dankwoord - Acknowledgments 199 III List of Abbreviations Akt Serine/threonine kinase ASD Autism spectrum disorder ATP Adenosin triphosphate BBB Blood-brain barrier BDNF Brain derived neurotrophic factor BP Bandpass BSA Bovine serum albumin C Complement CCL C-C motif chemokine CCR C-C motif chemokine receptor CD Cluster of differentiation CNS Central nervous system CNS Central nervous system CNTF Cilliary neurotrophic factor CR Complement receptor CSF (R) Colony stimulating factor (receptor) CSPGs Chondroitin sulphate proteoglycans CT-1 Cardiotrophin-1 CX3CR1 Chemokine (C-X3-C motif) receptor 1 CXCL C-X-C motif chemokine CXCR C-X-C motif chemokine receptor DAP12 DNAX activation protein of 12kDa DAPI 4',6-diamidino-2-phenylindole DMEM Dulbecco's Modified Eagle's Medium E Embryonic day ECM Extracellular matrix eGFP Enhanced green fluorescent protein ERK Extracellular signal–regulated kinases FAK Focal adhesion kinase FBS Fetal bovine serum FN Fibronectin GABA γ-aminobutyric acid GDNF Glial derived neurtrophic factor GE Ganglionic eminences GFAP Glial fibrillary acidic protein GLAST Glutamate aspartate transporter (G)M-CSF(R) (Granulocyt) macrophage coloniy-stimulating factor GTP Guanine triphosphate HBSS Hank's Balanced Salt Solution HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid HIV-1 Human type 1 immunodeficiency virus HS Horse serum HSC Hematopoietic stem cell Iba-1 Ionized calcium-binding adapter molecule 1 ICAM-1 Intercellular Adhesion Molecule 1 IFN Interferon IGF Insulin-like growth factor IL Interleukin iNOS Inducible nitric oxide synthase iPLA2 Calcium-independent phospholipase A2 KO Knockout LFA Lymphocyte function-associated antigen LGE Lateral ganglionic eminence V LIF Leukemia inhibitory factor LPS Lipopolysaccharide Mac-2 Macrophage-2 antigen MAPK Mitogen-activated protein kinases MCP-1 Monocyte chemotactic protein 1 MECP2 Methyl-CpG-binding protein 2 MEK Mitogen-activated protein kinase kinase MFI Median fluorescence intensity MGE Medial ganglionic eminences MIA Maternal immune activation MIP Macrophage inflammatory protein MMP Matrix metalloproteinase MP Myeloid progenitors mRNA Messenger ribonucleic Acid NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells NGF Nerve growth factor NO Nitric oxide NOS Nitric oxide synthase NOX NADPH oxidase NT Neurotrophin P Postnatal day P/S Penicillin Streptomycin PBS Phosphate-buffered saline PCD Programmed cell death PFA Paraformaldehyde PKA Protein kinase A PI3K Phosphatidylinositol 3-kinase PLC Phospholipase C PM Primary microglia Poly (I:C) Polyinosinic:polycytidylic acid RANTES Regulated on Activation, Normal T Cell Expressed and Secreted RGD Arginine-Glycine-Aspartate sequence Rpm Revolutions per minute RT Room temperature SDF-1 Stromal cell-derived factor 1 SFK Src family kinases SVZ Subventricular zone TGF-β Transforming growth factor-β TLR Toll like receptor TNF Tumour necrosis factor TTX Tetrodotoxin VEGF Vascular endothelial growth factor VEGFR-1 Vascular endothelial growth factor receptor 1 VZ Ventricular zone Wnt Wingless-type MMTV integration site family member VI CHAPTER 1 CHAPTER 1: General introduction and aims 1 General introduction and aims Why study microglia during brain development? The brain and spinal cord make up the central nervous system (CNS). These organs process all motor and sensory information and form the control center for all our daily activities. In the human CNS, approximately 100 billion neurons send electrochemical signals in dense networks and establish in total more than 600 trillion connections, called synapses that are necessary for us to breath, feel, move, and think [1, 2]. The CNS consists of neurons and glia, with the latter defined by Virchow in the 19th century as the cells that support the neurons by acting as a “glue” [3]. Depending on the brain region and age, roughly 50% of the cells in the brain are glia in humans, primates and rodents [4]. The largest and most important information-processing network in the mammalian brain is the neocortex, which consists of 20-25 billion neurons [5]. This is the outer layer of the cerebral hemispheres and it processes sensory information, controls motor output and mediates higher cognitive functions [1, 6]. This structure has a glia to neuron ratio of 3.76 and its cellular composition is highly conserved between humans, primates and rodents [4]. Glial cells can be subdivided into macroglia (astrocytes and oligodendrocytes) and microglia. The latter cell type constitutes 5-15% of all cells in the adult human brain and 6-18% of all neocortical cells [4, 7]. During development, one layer of germ cells called the neurectoderm, will generate these billions of neurons that eventually establish these trillions of connections by following highly conserved developmental programs.
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