A neuronal PIP3-dependent program of oligodendrocyte precursor recruitment and myelination
Georg Wieser
Doctoral thesis
Date of Examination:
2016-12-15
Date of issue:
2017-01-26
Advisor:
Goebbels, Sandra Dr.
Referee:
Nave, Klaus-Armin Prof. Dr.
Referee:
Brose, Nils Prof. Dr.
Referee:
Heinrich, Ralf Prof. Dr.
Persistent Address: http://hdl.handle.net/11858/00-1735-0000-002B-7D1F-A
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Abstract
English
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.
Keywords: OPC; Oligodendrocyte; Myelination; PTEN
