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Neurod Family Transcription Factors Regulate Corpus Callosum Formation and Cell Differentiation During Cerebral Cortical Development

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Neurod Family Transcription Factors Regulate Corpus Callosum Formation and Cell Differentiation During Cerebral Cortical Development Aus dem Institut für Cell und Neurobiologie der Medizinischen Fakultät Charité – Universitätsmedizin Berlin DISSERTATION NeuroD Family Transcription Factors Regulate Corpus Callosum Formation and Cell Differentiation during Cerebral Cortical Development zur Erlangung des akademischen Grades Doctor of Philosophy (PhD) Im Rahmen des International Graduate Program Medical Neurosciences vorgelegt der Medizinischen Fakultät Charité – Universitätsmedizin Berlin von Kuo Yan aus: Jinan, China Datum der Promotion: 5. Juni 2016 1 Table of Contents Abstract .................................................................................................................... 5 Zusammenfassung .................................................................................................. 7 1. Introduction ......................................................................................................... 9 1.1 Cerebral cortex development ………………………………………...................... 9 1.1.1 Layering and wiring of the neocortex ........................................................... 9 1.1.2 Formation of the corpus callosum ................................................................ 12 1.2 Basic helix-loop-helix transcription factors ........................................................ 13 1.2.1 NeuroD family transcription factors .............................................................. 14 1.2.2 NeuroD2/6 double deficient mice as a model for axogenesis study ............ 15 1.3 Ephrin-Eph signaling ......................................................................................... 17 1.3.1 Eph-Ephrin signaling in axon guidance ........................................................ 19 1.3.2 Diversified functions of ephrinAs mediated reverse signaling ……………… 21 1.4 Neurotrophin signaling ...................................................................................... 22 1.4.1 Ntrk2 downstream signaling ......................................................................... 23 1.4.2 The functions of neurotrophin signaling in nervous system ......................... 24 2. Aims...................................................................................................................... 25 3. Methods and Materials ....................................................................................... 27 3.1 Mouse mutants ................................................................................................. 27 3.2 Genotyping and polymerase chain reaction ……….......................................... 27 3.3 In utero electroporation..................................................................................... 28 3.4 Molecular cloning, constructs and mutagenesis ……....................................... 29 3.5 Bromodeoxyuridine pulse chase ……............................................................... 33 3.6 In situ hybridization ........................................................................................... 34 3.7 Immunohistochemistry and Immunocytochemistry ………………..................... 35 3.8 Microscopy and image acquisition .................................................................... 36 3.9 Tissue processing ............................................................................................. 37 3.10 Cell culture, transfection and neurotrophin stimulation ................................... 38 3.11 Luciferase Assay ............................................................................................. 38 3.12 Bicinchoninic acid assay and Western Blot …................................................. 40 3.13 Co-immunoprecipitation and pull-down assay ................................................ 42 3.14 Quantification for axonal fasciculation …………………................................... 43 2 3.15 Statistics ......................................................................................................... 43 4. Results ................................................................................................................. 44 Part I: NeuroD2/6 regulate corpus callosum formation via EfnA4 ………………..… 44 4.1 Restoration of NeuroD2 or NeuroD6 in DKO embryos rescues axon agenesis …………………………………………………………………………………. 44 4.2 Neuron identities and lamination are grossly normal in NeuroD2/6 DKO cortex ………………………………………………………………………………. 46 4.3 NeuroD2/6 regulate gene expression in upper layer neurons .......................... 47 4.4 Ephrin liagnds are down-regulated in NeuroD2/6 DKO cortical plate ............... 48 4.5 Restoration of EfnA4, but not of the other ephrins, rescues callosal agenesis ................................................................................................................. 50 4.6 Over-expression of EphA receptors does not rescue callosal agenesis in DKO …………………………………………………………………………………..... 51 4.7 A secreted variant of EfnA4 does not rescue callosal agenesis in DKO mice ................................................................................................................ 53 4.8 Expression patterns of potential EfnA4 co-receptors ........................................ 55 4.9 Generation and verification of dominant negative Ntrk2 and Ntrk3 .................. 56 4.10 EfnA4 interacts with Ntrk receptors in vitro ..................................................... 57 4.11 Function of EfnA4 in callosal axogenesis depends on Ntrk2, but not Ntrk3 ... 58 4.12 EfnA4/Ntrk2 interplay modulates Ntrk2 downstream signaling in vitro ........... 59 4.13 EfnA4/Ntrk2 interplay modulates Ntrk2 downstream signaling in vivo ........... 62 4.14 Ntrk2Y515F, but not Ntrk2Y816F, interferes with EfnA4 mediated rescue ........... 64 4.15 Quantification for callosal axon fasciculation ................................................. 65 4.16 Generation and verification of Eph-binding deficient EfnA4 variant ............... 68 4.17 EfnA4/Ntrk2 promoted callosal axogenesis depends on interaction with Eph receptors ................................................................................................. 69 4.18 Other potential downstream targets of NeuroD2/6 for axogenesis regulation ............................................................................................................... 70 Part II: NeuroD2/6 regulate cell differentiation during corticogenesis ………….…. 72 4.19 NeuroD1 expression is ectopically up-regulated in postmitotic neurons of NeuroD2/6 DKO neocortex and hippocampus ....................................................... 72 4.20 NeuroD2/6 inactivation affects the ratio of UL and DL neurons ..................... 74 3 4.21 Neurons in DL are selectively reduced in NeuroD2/6 DKO brains ................. 74 4.22 Defective differentiation of Tbr2+ basal progenitors in NeuroD2/6 DKO brains ……………………………………………………………………………….. 75 4.23 Birthdating analysis of ectopic Tbr2+ cells in NeuroD2/6 DKO embryos ........ 76 4.24 NeuroD6 is expressed in Tbr2+ cells in the SVZ/IZ ........................................ 77 4.25 Over-expressed Neuro2/6 promote the differentiation of Tbr2+ progenitors ... 78 4.26 Olig2+ progenitors are increased in NeuroD2/6 DKO neocortex ..................... 80 4.27 Expression of NeuroD6 and Olig2 is mutually exclusive .................................. 81 4.28 ISH based expression screen and more about potential NeuroD2/6 downstream targets .................................................................................................. 82 5. Discussion ............................................................................................................ 87 5.1 NeuroD2/6 control callosal axon growth cell intrinsically ................................... 87 5.2 NeuroD2/6 modulate gene expression in UL neurons without modifying cell identities and cortical lamination .............................................................................. 88 5.3 NeuroD family transcription factors redundantly regulate cell differentiation in genetically linked pathways ..................................................................................... 90 5.4 EfnA4 restoration facilitates partial and specific rescue of callosal agenesis .... 92 5.5 EfnA4/Ntrk2 reverse signaling promotes callosal axon fasciculation and guidance ………………………………………………………………………………….. 95 5.6 EfnA4/Ntrk2 interaction modulates the intracellular cascades of Ntrk2 in vitro and in vivo ............................................................................................................... 97 5.7 EfnA4/Ntrk2 functional reverse signaling depends on SHC-binding tyrosine ... 98 5.8 A hypothesized working model: EphA/EfnA4/Ntrk2 form a protein complex to modulate callosal axon guidance ....................................................................... 99 5.9 Dynamic balance of forward and reverse signals may count ………………..… 100 5.10 NeuroD2/6 regulate cell differentiation via both intrinsic and extrinsic mechanisms ………………..…………………………………………………………….. 101 6. References ........................................................................................................... 103 7. Affidavit (Eidesstattliche Versicherung) …………………………………..……... 111 8. Curriculum Vitae (My curriculum vitae does not appear in the electronic version of my dissertation for reasons of data protection) ......................................................... 113 9. Publication list .................................................................................................... 114 10. Acknowledgements …………………………………….……………………….….. 115 4
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