ELEVATION OF CERAMIDE WITHIN DISTAL NEURITES INHIBITS NEURITE GROWTH IN CULTURED RAT SYMPATHETIC NEURONS

Sphingolipids are abundant constituents of neuronal membranes and have been implicated in intracellular signaling. We show that two analogs of glycosphingolipid biosynthetic intermediates, fumonisin B-1 (which inhibits dihydroceramide synthesis) and -1-phenyl-2-palmitoylamino-3-m orpholino-1-propanol (PPMP) (which inhibits glucosylceramide synthesis ) decrease glycosphingolipid synthesis in rat sympathetic neurons. Alt hough both fumonisin and PPMP inhibit glycosphingolipid synthesis, the se inhibitors have differential effects on ceramide metabolism in axon s. threo-PPMP, but not erythro-PPMP or fumonisin, induces an accumulat ion of [H-3]palmitate-labeled ceramide and impairs axonal growth. More over, exogenously added, cell-permeable C-6-ceramide, but not C-6-dihy droceramide, mimicks the effect of PPMP. Our studies suggest that the lipid second messenger ceramide acts in distal axons, but not cell bod ies, as a negative regulator of neurite growth.