A role for EGF receptor signaling in oligodendrocyte development and repair

Children'S Research Institute, Washington DC

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Abstract

[unreadable] DESCRIPTION (provided by applicant): [unreadable] [unreadable] Permanent demyelination, the major pathology of multiple sclerosis, involves the disruption of axonal myelin, impairment of impulse transmission and neuronal damage. It is of therapeutic importance to re-populate the lesions with oligodendrocyte progenitors capable of differentiating and remyelinating damaged neurons. In the postnatal brain, mature oligodendrocytes originate from subventricular zone (SVZ) oligodendrocyte progenitor cells (OPCs), which express the proteoglycan NG2. The molecular signals that regulate OPC development and oligodendrocyte regeneration are still poorly defined. We have recently analyzed OPC migration in vitro and in vivo, and used a CNP-hEGFR mouse, in which all NG2+ OPCs overexpress the hEGFR, to demonstrate that EGFR plays a crucial role in supporting NG2+ cell migration to different brain regions, including the subcortical white matter. A preliminary analysis of the postnatal SVZ in the CNP- hEGFR mouse showed that overexpression of the EGFR stimulates proliferation of NG2+ progenitors and expands the endogenous pool of these cells. These expanded SVZ NG2+ cells also express the transcription factors Mashl and Olig2, and generate oligodendrocytes in vitro. We propose to use the CNP- hEGFR mouse to further define the developmental properties of NG2+Mash1+Olig2+ progenitors in the postnatal SVZ and to characterize their participation in oligodendrogenesis. We will then compare white matter development and myelination in the CNP-hEGFR with that in wild type (wt) mice. Finally, we will compare the regenerative and remyelinating potential of NG2+Mash1+Olig2+ progenitors from CNP-hEGFR mice with their wt counterpart in two animal models of demyelination- lysolecithin-induced focal demyelination and cuprizone-induced generalized demyelination. These analyses will reveal important roles for EGFR in neural progenitor cell proliferation and migration in the postnatal brain, and will offer new avenues to improve oligodendrocyte regeneration from neural progenitor after demyelination. Our proposed studies aim to shed light on crucial regulators of oligodendrocyte development and remyelination that are potentially useful in therapeutic strategies. [unreadable] [unreadable] [unreadable]