MODULATION OF THE NEUROFIBROMATOSIS TYPE-1 GENE-PRODUCT, NEUROFIBROMIN, DURING SCHWANN-CELL DIFFERENTIATION

Neurofibromin, the product of the neurofibromatosis type 1 (NF1) gene, is a approximately 250 kDa protein expressed predominantly in cortical neurons and oligodendrocytes in the central nervous system (CNS) and sensory neurons and Schwann cells in the peripheral nervous system (PNS). To gain insight into the biological role of neurofibromin in Schwann cells, the modulation of NF1 gene expression in a Schwann cell line (MT4H1) stimulated to either proliferate or differentiate in response to agents that elevate intracellular cAMP was examined. Untreated cells and cells exposed to mitogenic doses of forskolin (1-10 muM) or 8-bromo-cAMP (0.1 mM) expressed low levels of NF1 mRNA and the protein was barely detectable. High doses of forskolin (100 muM) or 8-bromo-cAMP (1 mM) induced the expression of both myelin P0 protein and neurofibromin with an identical time course. Although NF1 mRNA levels peaked within 1-6 hr, the rise in neurofibromin was not apparent until 24-48 hr and peaked 72 hr after treatment. P0 and neurofibromin were also coinduced by cell-cell contact in high density, untreated cultures. Moreover, differentiation initiated by either cAMP stimulation or high density culture conditions was associated with predominant expression of the type 2 NF1 mRNA isoform. In contrast, type I NF1 mRNA isoform expression was observed in untreated Schwann cells or those stimulated with mitogenic doses of forskolin or 8-bromo-cAMP. A switch from the type 1 neurofibromin that can efficiently down-regulate p21-ras to the type 2 isoform with reduced activity may facilitate a p21-ras signaling pathway associated with Schwann cell differentiation. (C) 1993 Wiley-Liss, Inc.