Understanding the cellular and molecular mechanisms that regulate the generation of oligodendrocytes, the myelinating cells of the vertebrate central nervous system is essential both to establish a comprehensive vision of neural development and to effectively generate new therapeutic approaches towards demyelinating diseases. In the last funding period we have made substantial gains in defining the location and molecular signaling that regulates the appearance of oligodendrocyte precursors and their dispersal in the developing spinal cord. In the current proposal we outline a series of approaches that are designed to further our understanding of the cellular and molecular interactions that promote later stages of oligodendrocytes development and to relate that information to the regulation of successful myelin repair in the adult CNS. Building on new approaches and recent preliminary data we outline 3 specific aims that investigate distinct but related aspects of oligodendrocyte development. In the first aim we will test the hypothesis that mature MBP+ oligodendrocytes influence the timing and success of spinal cord myelination as the direct producer of myelin and through feedback signals to OPCs. In addition we will determine whether a local postnatal depletion of MBP+ oligodendrocytes compromises myelin repair in the same region of the adult following a second insult. In the second aim we will characterize the role of GFAP+ astrocytes in the generation of the spinal cord oligodendrocyte lineage and myelination and the third aim will address the role of both mature oligodendrocytes and astrocytes in the control of remyelination in the adult spinal cord. These studies take advantage of a novel approach developed in the laboratory during the last funding period in which we are able to selectively eliminate distinct populations of mature oligodendrocytes and astrocytes in precise locations at any point in the developing and adult CNS. To accomplish this we have generated a series of transgenic animals in which we express an inducible caspase 9 (iCP9) off cell type specific promoters. Induction of the iCP9 through cross-linking with a small molecule variant of the cell and tissue permeable FK506 stimulates apoptosis specifically in the targeted population of cells. These animal models provide us with a unique opportunity to assess the consequences of selective cell loss on myelination and myelin repair in the intact vertebrate CNS. The data generated during the course of these studies will provide new directions for the development of therapies for demyelinating diseases such as multiple sclerosis.
The ability of the brain and spinal cord to function effectively depends on the precise communication between different populations of neurons. That communication in turn depends on the successful formation of myelin sheaths around target axons that allows for rapid and specific connection between individual neurons. In the brain and spinal cord that insulation is generated by oligodendrocytes that may wrap many different axonal segments. Although we have learned a considerable amount about the development of oligodendrocytes and their precursors there is still much fundamental information missing. The studies in this application are designed to identify the cellular interactions that regulate maturation and myelination by oligodendrocytes both during development and myelin repair. Such information will provide new targets for the treatment of demyelinating disease such as Multiple Sclerosis.
|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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