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The Journal of Neuroscience, August 6, 2003, 23(18):7207-7217

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Aberrant Growth and Differentiation of Oligodendrocyte Progenitors in Neurofibromatosis Type 1 Mutants

Michael R. Bennett,¹ Tilat A. Rizvi,¹ Saikumar Karyala,¹ Randall D. McKinnon,² and Nancy Ratner¹

¹Department of Cell Biology, Neurobiology, and Anatomy, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0521, and ²Neurosurgery, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854

Neurofibromatosis type 1 (NF1) patients are predisposed to learning disabilities, macrocephaly, and brain tumors as well as abnormalities on magnetic resonance imaging that are postulated to result from abnormal myelination. Here we show that Nf1+/- spinal cords in adult mice have more than twofold-increased numbers of NG2+ progenitor cells. Nf1-/- embryonic spinal cords have increased numbers of Olig2+ progenitors. Also, cultures from Nf1 mutant embryos with hemizygous and biallelic Nf1 mutations have dramatically increased numbers of CNS oligodendrocyte progenitor cells. In medium that allows growth of neuroepithelial cells and glial progenitors, mutant cells hyper-respond to FGF2, have increased basal and FGF-stimulated Ras-GTP, and fail to accumulate when treated with a farnesyltransferase inhibitor. Cell accumulation results in part from increased proliferation and decreased cell death. In contrast to wild-type cells, Nf1-/- progenitors express the glial differentiation marker O4 while retaining expression of the progenitor marker nestin. Nf1 mutant progenitors also abnormally coexpress the glial differentiation markers O4 and GFAP. Importantly, Nf1-/- spinal cord-derived oligodendrocyte progenitors, which are amplified 12-fold, retain the ability to form oligodendrocytes after in vivo transplantation. The data reveal a key role for neurofibromin and Ras signaling in the maintenance of CNS progenitor cell pools and also suggest a potential role for progenitor cell defects in the CNS abnormalities of NF1 patients.

Key words: NF1; progenitor; oligodendrocyte; FGF; brain; Ras

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Received May. 5, 2003; revised Jun. 10, 2003; accepted Jun. 17, 2003.

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