The objectives of this thesis were to investigate the intracellular signaling pathways involved in insulin-like growth factor-I (IGF-I)-mediated oligodendrocyte progenitor survival and proliferation; as well as to assess whether activation of muscarinic acetylcholine receptors (mAChR) could support the survival of these cells and to characterize the underlying mechanisms. The main signaling pathways studied were the PI3K (phosphatidylinositol 3-kinase)-PDK1 (3-phosphoinositide-dependent kinase-1)-Akt, the MEK/ERK (mitogen-activated protein kinase kinase/extracellular signal-regulated kinase and Src tyrosine kinases. / IGF-1 was found to protect oligodendrocyte progenitors from apoptosis induced by growth factor deprivation in a PI3K-dependent and MEK/ERK-independent manner. In addition, IGF-I activated Akt while inhibiting caspase-3 activation, and these effects were reversed by PI3K inhibition but not by inhibition of MEK1. Interestingly, PP2, a specific Src tyrosine kinase inhibitor, blocked tyrosine phosphorylation of Fyn and Lyn and activation of Akt stimulated by IGF-I, yet had no significant effects on caspase-3 activation or progenitor survival. Furthermore, while treatment with dominant negative Akt-mutants or a pharmacological inhibitor decreased Akt activity and reduced basal cell survival, IGF-I could partially rescue oligodendrocyte progenitors by decreasing caspase-3 activation. / IGF-I promoted oligodendrocyte progenitor proliferation through PI3K/Akt, MEK/ERK and Src tyrosine kinase pathways. Thus, IGF-I stimulated a transient phosphorylation of PDK1 and ERKI/2 and a rapid and sustained activation of Akt. Furthermore, inhibitors of PI3K, MEK1, and Src tyrosine kinases blocked ERK1/2 activation. / Similar to IGF-I, activation of mAChR significantly protected oligodendrocyte progenitors from apoptosis following growth factor withdrawal. This action was reversed by inhibitors of PI3K, Akt and Src tyrosine kinases, but not by MEK inhibitors. Furthermore, the acetylcholine analog carbachol blocked caspase-3 cleavage and stimulated tyrosine-phosphorylation of Fyn, a member of the Src tyrosine kinase family. Both Akt and ERK1/2 activation were dependent on the upstream action of the Src tyrosine kinases. In conclusion, we showed that PI3K/Akt promotes both survival and proliferation effects of IGF-I on oligodendrocyte progenitors, whereas MEK/ERK1/2 mediates only the mitogenic effect. Src tyrosine kinases act upstream of Akt and ERK1/2. Akt independent signaling downstream of PI3K is also implicated in IGF-I-stimulated cell survival. mAChRs play a role in the activation of Src tyrosine kinases and PI3K/Akt as well as in oligodendrocyte progenitor survival.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.111869 |
| Date | January 2006 |
| Creators | Cui, Qiao-Ling, 1963- |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Pharmacology & Therapeutics.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002584274, proquestno: AAINR32345, Theses scanned by UMI/ProQuest. |
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