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Functional Role of a Polysialic Acid- Carrying Proteolytic Fragment of the Neural Cell Adhesion Molecule NCAM in the Nervous System

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Functional Role of a Polysialic Acid- Carrying Proteolytic Fragment of the Neural Cell Adhesion Molecule NCAM in the Nervous System Functional role of a polysialic acid- carrying proteolytic fragment of the neural cell adhesion molecule NCAM in the nervous system DISSERTATION Zur Erlangung des Doktorgerades der Naturwissenschaften ( doctor rerum naturalium ) des Departments Biologie der Fakultät für Mathematik, Informatik und Naturwissenschaften an der Universität Hamburg Vorgelegt von NINAWESTPHAL Hamburg, 2017 Diese Arbeit wurde am Zentrum für Molekulare Neurobiologie Hamburg (ZMNH), im Institut für Biosynthese Neuraler Strukturen durchgeführt. Gutachter: Frau Prof. Dr. M. Schachner Herr Prof. Dr. T. Burmester Tag der Disputation: 07.03.2017 Contents Statement of Contribution ........................................................................................................................ I 1. Introduction ......................................................................................................................................... 1 1.1 Structure, isoforms and proteolytic processing of NCAM ........................................................................... 2 1.2. N-glycosylation of NCAM and attachment of polysialic acid ................................................................... 3 1.3 Functions of polysialylated NCAM in the central nervous system .............................................................. 5 1.4 Interaction of PSA and/or NCAM with other molecules.............................................................................. 6 1.5 PSA-NCAM- mediated downstream signalling ........................................................................................... 7 1.5.1 Fyn and focal adhesion kinase (FAK) dependent signal transduction .................................................. 8 1.5.2 Fibroblast growth factor (FGF)-receptor mediated signal transduction ................................................ 8 1.5.3 Protein kinase C (PKC) and MARCKS-dependent signal transduction ............................................... 9 2. Rationale and Aim of the study ......................................................................................................... 11 3. Material ............................................................................................................................................. 12 3.1 Animals ...................................................................................................................................................... 12 3.2 Cell lines..................................................................................................................................................... 12 3.3 Primers ....................................................................................................................................................... 12 3.4 Antibodies .................................................................................................................................................. 13 3.5 Reagents ..................................................................................................................................................... 15 3.6 Inhibitors .................................................................................................................................................... 17 3.7 Buffers and solutions .................................................................................................................................. 17 4. Methods ............................................................................................................................................. 22 4. 1 Primary cell culture / cell lines .................................................................................................................. 22 4. 2 Cell surface biotinylation and cell treatment ............................................................................................. 22 4. 3 Preparation of mouse brain tissue sections and coronal brain slices ......................................................... 23 4. 4 Polyethylene glycol precipitation of chicken NCAM antibody from egg yolk ................................................ 24 4. 5 Preparation of cytoplasmic fraction and microsome fractions .................................................................. 24 4. 6 Subcellular protein fractionation ............................................................................................................... 25 4. 7 Isolation of PSA-carrying proteins by immunoprecipitation (IP) and N-glycan digestion ....................... 26 4. 8 In vitro translocation and nuclear import assay ......................................................................................... 27 4. 9 S-nitrosylation assay ................................................................................................................................. 28 4. 10 Protein determination and precipitation .................................................................................................. 29 4. 11 Sodium dodecyl sulfate polyacrylamide gelelectrophoresis (SDS-PAGE) and immunoblot analysis .... 30 4. 12 Enzyme-linked immunosorbent assay (ELISA) ...................................................................................... 30 4. 13 Measurement of nitric oxide levels ......................................................................................................... 31 4. 14 Proximity ligation assay .......................................................................................................................... 32 4. 15 Immunoelectron microscopy ................................................................................................................... 33 4. 16 RNA isolation and microarray analysis ................................................................................................... 34 4. 17 Quantitativ real-time polymerase chain reaction (qRT-PCR) ................................................................. 35 4. 18 Statistical analysis ................................................................................................................................... 37 5. Results ............................................................................................................................................... 39 5. 1 Nuclear import of a PSA-carrying proteolytic NCAM fragment in cultured cerebellar neurons .............. 39 5.2 PSA co-localizes with histone H1 in nuclei of wildtype cerebellar neurons .............................................. 43 5.3 Detection of nuclear PSA by immunoelectron microscopy ..................................................................... 45 5.4 The nuclear PSA-carrying NCAM fragment is generated by matrix-metalloproteases MMP-2 and MMP-9 upon treatment with NCAM antibody ...................................................................................... 46 5.5 The PSA-carrying NCAM fragment is transported from the plasma membrane to the nucleus via late endosomes ................................................................................................................................................ 48 5.6 The PSA-carrying NCAM fragment is released from endosomes into the cytoplasm in a calmodulin-dependent manner ....................................................................................................................... 50 5.7 Binding of PSA-NCAM to PC4 and cofilin in nuclei of dissociated cerebellar neurons and cerebellar tissue................................................................................................................................................................. 53 5.7.1 PC4 and cofilin contribute to the translocation of the PSA-carrying NCAM fragment from the cytoplasm into the nucleus ........................................................................................................................... 57 5.9 NCAM antibody, FGF-2 and the MARCKS-derived ED peptide trigger phosphorylation of MARCKS and induce the generation and nuclear import of the PSA-NCAM fragment ........................... 58 5.10 The generation of the PSA-carrying NCAM fragment is induced by different pathways which require activation of the FGF-receptor .......................................................................................................... 60 5.10.1 The FGF-2- and NCAM antibody-induced generation and nuclear import of the PSA-carrying NCAM fragment depends on calmodulin-induced NO synthesis and NO-mediated activation MMP-9 .... 61 5.10.2 MARCKS-ED peptide-induced generation and nuclear import of the PSA-carrying NCAM fragment reqiures FGF-receptor-mediated PKC-, PLC-, PLD-, and PI3K-dependent activation of MMP-2 ........................................................................................................................................................ 65 5.11 Nuclear PSA-NCAM is involved in the circadian rhythm in vitro and in vivo ........................................ 69 5.11.1 Nuclear import of the PSA-NCAM fragment affects mRNA expression of the clock-related genes CLOCK and Per-1 in cerebellar neurons ........................................................................................... 69 5.11.2 Nuclear PSA-NCAM fragment levels in the cerebellum and suprachiasmatic nucleus are associated with reduced expression of clock-related genes ......................................................................... 72 5.12 PSA-carrying NCAM co-localizes with histone H1 in vivo during the light/dark cycle ................... 76
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