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Mechanisms Regulating Gabaergic Neurogenesis in the Developing Mouse Midbrain

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Mechanisms Regulating Gabaergic Neurogenesis in the Developing Mouse Midbrain WISSENSCHAFTSZENTRUM WEIHENSTEPHAN FÜR ERNÄHRUNG, LANDNUTZUNG UND UMWELT LEHRSTUHL FÜR ENTWICKLUNGSGENETIK Mechanisms regulating GABAergic neurogenesis in the developing mouse midbrain Clara Elisabeth Teresa Agathe Tabea Zoe Wende Vollständiger Abdruck der von der Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigten Dissertation. Vorsitzender: Univ. Prof. Dr. S. Scherer Prüfer der Dissertation: 1. Univ. Prof. Dr. W. Wurst 2. Univ. Prof. Dr. H. Lickert Die Dissertation wurde am 28.07.2015 bei der Technischen Universität München eingereicht und durch die Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt am 12.11.2015 angenommen. Für meinen Großvater 2 1 CONTENT 2 SUMMARY ......................................................................................................................................................... 7 3 ZUSAMMENFASSUNG .................................................................................................................................... 9 4 REVIEW OF LITERATURE ......................................................................................................................... 11 4.1 THE NEUROTRANSMITTER Γ-AMINOBUTYRIC ACID ..................................................................................... 11 4.1.1 TWO ENZYMES FOR THE SYNTHESIS OF GABA ......................................................................................................... 11 4.1.2 GABAERGIC SIGNALING ................................................................................................................................................ 13 4.1.3 GABA SIGNALING IN THE IMMATURE BRAIN ............................................................................................................ 16 4.2 DEVELOPMENT OF THE VERTEBRATE CNS .................................................................................................. 18 4.2.1 NEURAL INDUCTION ...................................................................................................................................................... 18 4.2.1.1 Patterning oF the neural tube ........................................................................................................................... 19 4.2.1.2 A/P patterning oF the brain ............................................................................................................................... 20 4.2.1.3 D/V patterning oF the developing brain ....................................................................................................... 21 4.3 DIFFERENTIATION OF NEURONS IN THE BRAIN ........................................................................................... 23 4.3.1 COORDINATION OF NEURONAL FATE: REGULATION OF NEUROGENESIS .............................................................. 23 4.3.2 NOTCH-SIGNALING AND LATERAL INHIBITION ....................................................................................................... 24 4.3.3 BHLH-TFS ...................................................................................................................................................................... 26 4.3.4 HES GENES ....................................................................................................................................................................... 27 4.3.5 PRONEURAL PROTEINS .................................................................................................................................................. 28 4.3.6 NEURONAL SUBTYPE SPECIFICATION IN PROLIFERATING PROGENITORS ............................................................ 29 4.3.7 NEURONAL SUBTYPE SPECIFICATION IN POSTMITOTIC NEURONS. ........................................................................ 29 4.4 SPECIFICATION OF GABAN IN DIFFERENT BRAIN AREAS ........................................................................... 30 4.5 GABAERGIC NEUROGENESIS IN THE MB ..................................................................................................... 31 4.5.1 SUBPOPULATION OF GABAN IN THE MATURE MB AND THEIR FUNCTION ......................................................... 31 4.5.2 PATTERNING OF THE EMBRYONIC MB NEUROEPITHELIUM ................................................................................... 32 4.5.3 MIGRATION OF DIFFERENT MB GABA POPULATIONS ............................................................................................ 34 4.5.4 MGN AND MASH1: TWO KEY FACTORS FOR THE EARLY SPECIFICATION OF MB GABAN .............................. 34 4.5.4.1 Megane ....................................................................................................................................................................... 35 4.5.4.2 Expression pattern oF Mgn ................................................................................................................................ 35 4.5.4.3 MGN is a cell Fate determinant For MB GABAn .......................................................................................... 36 3 4.5.5 THE BHLH TFS MASH1 AND MGN HAVE A SIMILAR FUNCTION REGARDING SPECIFICATION OF MB GABAN ........................................................................................................................................................................................... 37 4.6 SUBTYPE SPECIFICATION AND MAINTENANCE IN POSTMITOTIC MB GABAN PRECURSORS ..................... 38 4.6.1 GATA AND TAL TFS ..................................................................................................................................................... 38 4.6.2 LIM HOMEOBOX1 AND BRN3A ...................................................................................................................................... 40 4.7 SIMILARITIES OF GENETIC CASCADES TO THE MB ...................................................................................... 40 5 AIM OF THE STUDY .................................................................................................................................... 42 6 MATERIALS ................................................................................................................................................... 43 6.1 CHEMICALS & SUBSTANCES .......................................................................................................................... 43 6.2 INSTRUMENTS ............................................................................................................................................... 46 6.3 CONSUMABLES & OTHERS ............................................................................................................................ 48 6.4 STOCK SOLUTIONS AND BUFFERS ................................................................................................................. 49 6.5 KITS ............................................................................................................................................................... 53 6.6 OLIGONUCLEOTIDES FOR GENOTYPING ....................................................................................................... 54 6.7 WORK WITH BACTERIA ................................................................................................................................ 55 6.7.1 ESCHERICHIA COLI (E. COLI) STRAINS ......................................................................................................................... 55 6.7.2 MEDIA AND AGAR .......................................................................................................................................................... 55 6.8 ENZYMES ........................................................................................................................................................ 56 6.9 PLASMIDS FOR IN SITU HYBRIDIZATION ...................................................................................................... 57 6.10 CO-IMMUNOPRECIPITATION (CO-IP) AND WESTERN BLOT (WB) ........................................................ 58 6.10.1 PRIMARY ANTIBODIES FOR CO-IP AND WB ........................................................................................................... 58 6.10.2 SECONDARY ANTIBODIES FOR CO-IP AND WB ...................................................................................................... 58 6.11 IMMUNOHISTOCHEMISTRY (IHC) ............................................................................................................. 58 6.11.1 PRIMARY ANTIBODIES FOR IHC ................................................................................................................................ 58 6.11.2 SECONDARY ANTIBODIES FOR IHC .......................................................................................................................... 59 6.13 MOUSE STRAINS ......................................................................................................................................... 60 7 METHODS ...................................................................................................................................................... 61 7.1 MOUSE HUSBANDRY ...................................................................................................................................... 61 7.2 MOLECULAR BIOLOGY
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