Despite its importance, the intercellular signals that regulate the formation of myelin during development, are not known. The investigator has shown that Notch receptor is expressed by oligodendrocyte precursor cells and that activation of the receptor inhibits the production in vitro of differentiated oligodendrocytes by optic nerve neuroglial progenitor cells. Furthermore, retinal ganglion cells in vivo express a Notch receptor ligand in a temporal pattern consistent with its acting as a regulator of oligodendrocyte production and myelin formation in developing optic nerve. The studies proposed in this application address the hypothesis that Notch receptor activation governs the production of oligodendrocytes and thereby establishes spatial and temporal patterns of myelination during development and further that Notch also has a role in the regulation of adult oligodendrocyte progenitors. The experimental approach uses a retinal ganglion cell/ oligodendrocyte precursor cell culture system developed by the investigator and also includes extensive studies in vivo. In both systems, a variety of techniques to perturb Notch signaling will be employed and the effect on oligodendrocyte differentiation and myelination will be determined. Tests of four specific questions are listed as specific aims: (1) does the Notch pathway regulate the timing of oligodendrocyte generation and myelination? (2) does the Notch pathway regulate adult oligodendrocyte precursor cell development? (3) does the Notch pathway regulate the localization of oligodendrocyte generation and myelination? and (4) how does the Notch pathway inhibit oligodendrocyte differentiation?
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