The neuroepithelium gives rise to all the major classes of cells in the mature vertebrate CNS including neurons, astrocytes and oligodendrocytes. In most cases, the regulation of commitment of neuroepithelial cells to a specific fate and the control of precursor cell migration and differentiation is unknown. We have demonstrated that oligodendrocyte precursors in the developing rat spinal cord are initially located only in ventral regions of the spinal cord and during subsequent development migrate dorsally where they differentiate into myelin forming cells. More recently we identified a specific location in the ventral ventricular zone of the chick spinal cord in which precursors become committed to oligodendrocytes, and we described a ventral to dorsal gradient of oligodendrocyte differentiation. These observations led us to propose that the notochord, a ventrally located transient embryonic structure regulates the development of spinal cord oligodendrocytes. To determine if signals from the notochord influence the pattern of oligodendrocyte development, and whether the notochord is essential for the subsequent development of spinal cord oligodendrocytes, we will perform notochord transplantation and ablation studies in chick and Xenopus embryos. In order to myelinate CNS regions devoid of intrinsic oligodendrocyte precursors and to ameliorate pathologically demyelinated adult CNS regions, oligodendrocyte precursors must migrate considerable distances. We demonstrated that rat optic nerve oligodendrocytes were derived from progenitor cells that migrated from the brain during development, while the myelination of the complete spinal cord is dependent on the ventral to dorsal migration of oligodendrocyte precursors. Based on these studies we propose that there are-distinct pathways utilized for migration of oligodendrocyte precursors in the CNS. We have recently developed an immunolabeling paradigm which for the first time allows us to examine directly the characteristics of actively migrating oligodendrocyte precursors in vivo. Using a combination of light and electron microscopic assays, we will determine the cellular substrates of oligodendrocyte precursor migration in the intact CNS. Further, to identify the molecular mechanisms mediating oligodendrocyte precursor migration, in vivo antibody perturbation studies will be compared with the analysis of oligodendrocyte precursor migration over defined molecular substrates in vitro. These studies will provide new and important information on the regulation of oligodendrocyte development in the vertebrate CNS. Such information is essential for designing successful approaches to induce remyelination following injury or demyelinating diseases such as multiple sclerosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS030800-03
Application #
2037553
Study Section
Neurology B Subcommittee 2 (NEUB)
Program Officer
Small, Judy A
Project Start
1995-01-01
Project End
1997-12-31
Budget Start
1997-01-01
Budget End
1997-12-31
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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Sargent, Alex; Bai, Lianhua; Shano, Genevieve et al. (2017) CNS disease diminishes the therapeutic functionality of bone marrow mesenchymal stem cells. Exp Neurol 295:222-232
Pajoohesh-Ganji, Ahdeah; Miller, Robert H (2016) Oligodendrocyte ablation as a tool to study demyelinating diseases. Neural Regen Res 11:886-9
Luo, Fucheng; Zhang, Jessie; Burke, Kathryn et al. (2016) The Activators of Cyclin-Dependent Kinase 5 p35 and p39 Are Essential for Oligodendrocyte Maturation, Process Formation, and Myelination. J Neurosci 36:3024-37
Sargent, Alex; Miller, Robert H (2016) MSC Therapeutics in Chronic Inflammation. Curr Stem Cell Rep 2:168-173
Tognatta, Reshmi; Miller, Robert H (2016) Contribution of the oligodendrocyte lineage to CNS repair and neurodegenerative pathologies. Neuropharmacology 110:539-547
Caprariello, Andrew V; Batt, Courtney E; Zippe, Ingrid et al. (2015) Apoptosis of Oligodendrocytes during Early Development Delays Myelination and Impairs Subsequent Responses to Demyelination. J Neurosci 35:14031-41
Zuchero, J Bradley; Fu, Meng-Meng; Sloan, Steven A et al. (2015) CNS myelin wrapping is driven by actin disassembly. Dev Cell 34:152-67
Najm, Fadi J; Madhavan, Mayur; Zaremba, Anita et al. (2015) Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo. Nature 522:216-20

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