The factors involved in the regulation of myelin sheath formation, which is essential to the proper functioning of the nervous system, are still poorly understood. In this proposal, we will test the hypothesis that the timing and localization of myelination are controlled by regulating the development of myelinating oligodendrocytes. We will specifically focus on the role of the Notch signaling pathway, which has recently been shown to strongly inhibit oligodendrocyte differentiation in vitro. Oligodendrocyte precursor cells constitutively express the Notch1 receptor. Nearby retinal ganglion cells express the Notch ligand Jagged1 early in development, and downregulate its expression in a manner which temporally parallels the onset of optic nerve myelination. Two hypotheses were suggested by this data, which we propose to test here. These two hypotheses are: (1) the Notch pathway may control the timing of optic nerve myelination, and (2) the Notch pathway may control the localization of myelination (i.e determine which axons are myelinated and which remain unmyelinated). We will take two main approaches to address these questions. First, we will attempt to determine whether we can promote myelination in co-cultures of oligodendrocytes and neurons by disrupting Notch-mediated signaling. Second, we will attempt to perturb Notch signaling in vivo by a variety of methods to observe what effects, if any, this has on the timing and localization of myelination in the developing nervous system. A greater understanding of the mechanisms that normally regulate myelin formation may allow for the development of new treatments for demyelinating diseases such as optic neuritis and Multiple Sclerosis.
