The prevailing notion that mammalian spinal cord oligodendrocyte precursors arise from restricted regions of the ventral ventricular zone as a result of direct signaling by sonic hedgehog appears to require revision. Dorsal regions of the spinal cord generate oligodendrocytes, as do multiple domains in more rostral CNS regions. Perhaps more compelling, oligodendrocytes can be generated in the total absence of Shh. We propose that commitment of cells to the oligodendrocyte lineage is regulated not by global signals but by local cell-cell interactions that preferentially occur in particular regions of the ventricular zone. Consistent with this hypothesis we have found that the appearance of OPCs is discontinuous along the rostral-caudal axis in the ventral ventricular zone and that interspersed between these cells are neuronal precursors suggesting that neuronally derived signals regulate the initiation of oligodendrogenesis. Support for this hypothesis comes from our recent studies demonstrating that retinal neurons are necessary and sufficient to promote oligodendrogenesis. In this proposal we will extend these studies to develop a clearer understanding of the environmental regulation of early oligodendrogenesis. In the first aim we will examine whether the ability to induce OPCs is a characteristic shared by multiple populations of neurons including those in the PNS, and characterize the signaling pathways responsible. Our preliminary data suggest that electrical activity is critical for the ability of neurons to induce oligodendrocyte precursors and in the second aim we propose to test this hypothesis in vitro and in vivo. How the population size of oligodendrocytes and their precursors are regulated during development is unclear. We propose that cell numbers are dynamically controlled to match environmental needs. To directly test this hypothesis in vivo we will use a novel cell type specific depletion approach to locally eliminate mature oligodendrocytes in aim 3 and OPCs in aim 4. Analyses of the responses to oligodendrocyte lineage cells to stage specific deletion will identify the major regulatory steps in oligodendrocyte development and provide novel targets for therapeutic intervention in demyelinating diseases such as Multiple Sclerosis.

Public Health Relevance

Myelination is the fatty insulation that surrounds the processes of neurons and allows them to communicate rapidly with each other. In the brain and spinal cord, myelin is made by oligodendrocytes and they are essential to allow the adult nervous system to function correctly. How oligodendrocytes are formed is not well understood and the studies in this application will identify the environmental signals that promote their initial appearance and control the number of oligodendrocyte lineage cells in the mature central nervous system. Such information will provide new targets for the development of treatments for demyelinating diseases such as Multiple Sclerosis.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-J (02))
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Owens, David F
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Case Western Reserve University
Schools of Medicine
United States
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Bai, Lianhua; Hecker, Jordan; Kerstetter, Amber et al. (2013) Myelin repair and functional recovery mediated by neural cell transplantation in a mouse model of multiple sclerosis. Neurosci Bull 29:239-50
Najm, Fadi J; Lager, Angela M; Zaremba, Anita et al. (2013) Transcription factor-mediated reprogramming of fibroblasts to expandable, myelinogenic oligodendrocyte progenitor cells. Nat Biotechnol 31:426-33
Kerstetter, Amber E; Miller, Robert H (2012) Isolation and culture of spinal cord astrocytes. Methods Mol Biol 814:93-104
Moore, Craig S; Milner, Richard; Nishiyama, Akiko et al. (2011) Astrocytic tissue inhibitor of metalloproteinase-1 (TIMP-1) promotes oligodendrocyte differentiation and enhances CNS myelination. J Neurosci 31:6247-54
Yang, Yan; Lewis, Rebecca; Miller, Robert H (2011) Interactions between oligodendrocyte precursors control the onset of CNS myelination. Dev Biol 350:127-38
Najm, Fadi J; Zaremba, Anita; Caprariello, Andrew V et al. (2011) Rapid and robust generation of functional oligodendrocyte progenitor cells from epiblast stem cells. Nat Methods 8:957-62
Fyffe-Maricich, Sharyl L; Karlo, J Colleen; Landreth, Gary E et al. (2011) The ERK2 mitogen-activated protein kinase regulates the timing of oligodendrocyte differentiation. J Neurosci 31:843-50
Miller, Robert H; Fyffe-Maricich, Sharyl L (2010) Restoring the balance between disease and repair in multiple sclerosis: insights from mouse models. Dis Model Mech 3:535-9
Tsai, Hui-Hsin; Macklin, Wendy B; Miller, Robert H (2009) Distinct modes of migration position oligodendrocyte precursors for localized cell division in the developing spinal cord. J Neurosci Res 87:3320-30
Caprariello, A V; Miller, R H; Selkirk, S M (2009) Foamy virus as a gene transfer vector to the central nervous system. Gene Ther 16:448-52

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