Myelin is a multilamellar tightly compacted membrane that surrounds most of the axons in the central nervous system (CNS). Myelin is formed by oligodendrocytes and functions as an insulator so that propagation of neuronal action potentials can occur rapidly via saltatory conduction. Failure to form myelin or destruction of myelin can have debilitating and often fatal consequences. The production of new oligodendrocytes in some instances can restore myelin and neurological function. The long-term goal of this application is to understand the mechanisms that regulate oligodendrocyte production and myelination in the developing CNS. Oligodendrocytes are generated from a progenitor cell (OPC) that is abundant in developing and adult brains. The present application will test the hypothesis that platelet-derived growth factor-A (PDGF-A) is a limiting factor in the production of oligodendrocyte in the CNS. This hypothesis is based on the following. 1) PDGF-A is an obligate mitogen for OPC's in vivo 2) OPC division is a requisite for oligodendrocyte production, 3) Oligodendrocyte production is locally regulated and not always linked to OPC production, and 4) Overexpression of PDGF increases oligodendrocyte number in developing and adult brain. Studies in Specific Aim 1 will establish if PDGF-A expression correlated with oligodendrocyte production in the cerebral cortex and optic nerve. Those in Specific Aim 2 will investigate the role of viable axons in PDGF-A expression, OPC proliferation and oligodendrocyte production.
Specific Aims 3 -6 will investigate the fate of overproduced OPC and oligodendrocytes in mice that overexpress PDGF-A. Recent studies from the laboratory indicate that oligodendrogenesis during remyelination in MS brain recapitulates many of the aspects of oligodendrogenesis in development. The studies outlined in this application should provide valuable insight into the mechanisms of oligodendrogenesis and hopefully identify new therapeutic targets that may enhance remyelination in human diseases such as Multiple Sclerosis.
| Wu, Chuanshen; Chang, Ansi; Smith, Maria C et al. (2009) Beta4 tubulin identifies a primitive cell source for oligodendrocytes in the mammalian brain. J Neurosci 29:7649-57 |
| Staugaitis, Susan M; Trapp, Bruce D (2009) NG2-positive glia in the human central nervous system. Neuron Glia Biol 5:35-44 |
| Power, C; Kong, P A; Trapp, B D (1996) Major histocompatibility complex class I expression in oligodendrocytes induces hypomyelination in transgenic mice. J Neurosci Res 44:165-73 |
