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dc.contributor.advisor Goebbels, Sandra Dr.
dc.contributor.author Wieser, Georg
dc.date.accessioned 2017-01-26T10:43:59Z
dc.date.available 2017-01-26T10:43:59Z
dc.date.issued 2017-01-26
dc.identifier.uri http://hdl.handle.net/11858/00-1735-0000-002B-7D1F-A
dc.language.iso eng de
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc 570 de
dc.title A neuronal PIP3-dependent program of oligodendrocyte precursor recruitment and myelination de
dc.type doctoralThesis de
dc.contributor.referee Nave, Klaus-Armin Prof. Dr.
dc.date.examination 2016-12-15
dc.description.abstracteng Evolution of myelin has enabled rapid impulse propagation and development of complex brain circuitry. However, the in vivo mechanisms that trigger and orchestrate proliferation of oligodendrocyte precursor cells (OPCs), differentiation of OPCs into oligodendrocytes, and myelination in central nervous system (CNS) have remained unclear. Neuregulin-1/ErbB signaling, which controls virtually all aspects of peripheral myelination by Schwann cells is not essential for myelination in the CNS. Moreover, the identification of several promyelination factors made by astrocytes and microglial cells, the responsiveness of oligodendrocytes to ubiquitously expressed growth factors and their ability to myelinate artificial nanofibers has raised questions about the cellular origin of the key signals that control CNS myelination. To particularly address the impact of axonal signals in vivo, we studied the cerebellum of mice, in which the axons of granule cell neurons (referred to as “parallel fibers”) within the molecular layer are naturally of small caliber and unmyelinated. By conditional inactivation of the lipid phosphatase PTEN, we experimentally enhanced PI(3,4,5)P3-dependent Akt/mTOR downstream signaling specifically in granule cells, which subsequently lead to a significant increase in parallel fiber (Pf) diameters. Most importantly, this increase was tightly associated with the proliferation of OPCs, the differentiation of oligodendrocytes in the molecular layer, and the de novo myelination of up to 40% of all Pf at 1 year of age. While the synaptic input to OPCs was unchanged, gene expression profiling of laser captured mutant granule cell layers identified proteins, such as FGF1, Pleiotrophin, Timp3, Thymosin beta 4, and Activin A, as novel regulators of OPC proliferation, oligodendrocyte differentiation, and/or myelin growth. We conclude that activation of neuronal, PI(3,4,5)P3-dependent downstream signaling pathways can be sufficient to promote the entire program of OPC recruitment and CNS myelination. de
dc.contributor.coReferee Brose, Nils Prof. Dr.
dc.contributor.thirdReferee Heinrich, Ralf Prof. Dr.
dc.subject.eng OPC de
dc.subject.eng Oligodendrocyte de
dc.subject.eng Myelination de
dc.subject.eng PTEN de
dc.identifier.urn urn:nbn:de:gbv:7-11858/00-1735-0000-002B-7D1F-A-7
dc.affiliation.institute Biologische Fakultät für Biologie und Psychologie de
dc.subject.gokfull Biologie (PPN619462639) de
dc.identifier.ppn 877957096

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