Cellular Mechanisms of Oligodendrocyte Myelination

Trapp, Bruce

Abstract

Based on location, morphology, and molecular phenotype, we have identified three distinct stages of oligodendrocyte lineage in developing rodent brain: oligodendrocyte progenitors, premyelinating oligodendrocytes, and myelinating oligodendrocytes. The objective of this proposal is to obtain a better understanding of cellular and molecular events that regulate oligodendrocyte differentiation (Specific Aim 1) and CNS myelination (Specific Aim 2).
Specific Aim 1 A will determine the appearance and distribution of oligodendrocyte progenitors, premyelinating oligodendrocytes, and myelinating oligodendrocyte in the mouse optic nerve. These data will serve as a baseline for those in Specific Aim 1C which investigate how axonal transection ad ablation of action potentials affect oligodendrocyte lineage in optic nerve.
Specific Aim 1 B will phenotype optic nerve cells undergoing programmed cell death and determine the average life span of a premyelinating oligodendrocyte. Studies in Specific Aim 1D will determine how overexpression of the most studied oligodendrocyte trophic factor, PDGF, affects oligodendrocyte lineage during normal development and after optic nerve transection or ablation of optic nerve action potentials. The second part of the proposal will characterize changes in myelin protein expression and microtubule organization as oligodendrocytes mature from a premyelinating (nonpolarized) to a myelinating (polarized) cell. Studies in Specific Aim 2B will identify regions (MAG and MOG) polypeptides that are responsible for their delivery to myelin and nonmyelin surface membranes. The studies outlined in the proposal will provide new and valuable insights into cellular and molecular mechanisms of oligodendrocyte differentiation and myelination that will prove valuable in understanding and treating diseases of myelin.