Actively myelinating oligodendrocytes: signaling mechanisms and response to injury, The

Abstract

The actively myelinating oligodendrocyte is vital for the normal development and proper function of the central nervous system (CNS). Despite significant progress in recent years, many fundamental questions remain regarding the cellular and molecular properties of oligodendrocytes. In this dissertation, we first sought to identify and characterize putative negative regulators of CNS myelination. We identified Shp2, a protein tyrosine phosphatase, as a potential negative regulator of CNS myelination using a candidate based approach and expression profiling of mRNA and protein during development in wild type and hypermyelinating mutant mice. We then characterized the functional role of oligodendrocyte Shp2 using inducible and conditional transgenic mice. We demonstrated that Shp2 regulated oligodendrocyte differentiation during postnatal development and acted as a transient brake during early myelin formation. Shp2 also regulated the timely remyelination following experimental demyelination. The second objective of this project was to examine the responses of the actively myelinating oligodendrocyte, which are enriched in the brain during late pediatric development, to ischemic injury. Using an established mouse model of experimentally induced reversible cerebral ischemia, we demonstrated that actively myelinating oligodendrocytes in the late pediatric brain were uniquely resistant to ischemia-induced damage compared to adult mice with the same injury. We showed that this difference could be due to pediatric oligodendrocytes having a more robust anti-oxidant capacity. We also exmined other glial responses unique to pediatric stroke and found that astrogliosis, fibrosis, NG2-cell responses and vascular integrity were all different in pediatric compared to adult animals. Combined, these differences in stroke response led to greater long-term tissue preservation in pediatric mice. Taken together, this thesis provides significant improvements to our understanding of the actively myelinating oligodendrocyte, both during development and following injury. These results could influence our understanding of prominent neurological diseases, such as multiple sclerosis and stroke.