© 2005 The Japanese Biochemical Society
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Glycosphingolipid Synthesis Inhibitor Represses Cytokine-Induced Activation of the Ras-MAPK Pathway in Embryonic Neural Precursor Cells
1 21st Century COE program "Cell Fate Regulation Research and Education Unit"; 2 Department of Cell Fate Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811; and 3 Department of Biochemistry, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara 228-8555
To whom correspondence should be addressed. Phone/Fax: +81-96-373-6610, E-mail: taga{at}kaiju.medic.kumamoto-u.ac.jp
Neuronal and glial cells in the central nervous system are generated from common neural precursor cells during development. To evaluate the functions of glycosphingolipids (GSLs) in neural precursor cells, neuroepithelial cells (NECs) were prepared from mouse embryos (E14.5), and the effects of an inhibitor of glucosylceramide synthesis, d-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), on NECs was investigated. In PDMP-treated NECs, the expression of GD3, a major ganglioside of NECs, disappeared. We found that basic fibroblast growth factor (bFGF)–induced proliferation and extracellular signal–regulated kinase (ERK) activation were repressed in PDMP-treated NECs. Leukemia inhibitory factor (LIF)–induced ERK activation was also abolished in PDMP-treated NECs, suggesting that PDMP specifically represses the Ras-MAPK pathway. bFGF-induced activation of the Ras-MAPK pathway in NECs is dependent on GSL-enriched microdomains, lipid rafts. The organization of lipid rafts and the distribution of Ras and Grb2-SOS in the microdomains were not affected. However, Ras activation was repressed in PDMP-treated NECs. In PDMP-treated NECs, some neuronal genes were up-regulated and glial genes were down-regulated. These results suggest that GSLs might be involved in the proliferation, survival, signal transduction and differentiation of NECs.
* Present address: Program in Developmental Neurobiology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, 1120 15th Street-CA4040, Augusta, GA30912, USA.
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