The complexity of sphingolipid metabolism in the modulation of neuronal development.

摘要

The lipid mediators, ceramide and sphingosine-1-phosphate (S1P), have multipotential roles in survival, migration, and differentiation of neurons depending on concentration, cell type, and developmental stage. Although exogenous ceramide has been reported to cause neuronal apoptosis, the role of endogenous ceramide has not been previously evaluated. Both ceramide and bacterial sphingomyelinase result in time- and dose-dependent increases in apoptosis of cerebellar granule cells and cortical neurons. In addition, the extent of apoptosis induced by trophic factor withdrawal or etoposide treatment correlates with endogenous ceramide increases, suggesting that ceramide produced by sphingomyelinase results in neuronal death.; There are two isoforms of sphingosine kinase (SphK), the enzyme that forms S1P by sphingosine phosphorylation. Traditionally, addition of S1P or stimulation of SphK has been associated with survival. However, recent reports suggest that the effects of SphK activation may be isoform specific. Unlike SphK1 which promotes cellular survival, SphK2 induces apoptosis in PC12 cells. Mutational analysis demonstrates that this requires both the catalytic domain of SphK2 and a putative BH3 domain. Consistent with the presence of a BH3 domain, pharmacological inhibitors suggest mitochondrial calcium regulation is involved. Since SphK2, but not SphK1, is translocated to mitochondria during serum starvation, its cellular location may modulate the diverse effects of SphK.; Neurite extension following activation of the tyrosine kinase receptor TrkA by nerve growth factor (NGF) involves complex signaling pathways, including the stimulation of SphK1. In PC12 cells and dorsal root ganglion neurons, NGF differentially transactivates the S1P receptors, S1P1, S1P2, and S1P5, in a SphK1-dependent manner, as determined with specific inhibitors and siRNA targeted to SphK1. NGF-induced neurite extension was suppressed by downregulating S1P1 expression with antisense RNA. Conversely, transactivation of S1P1 by NGF markedly enhanced neurite extension and stimulation of Rac, important for the cytoskeletal changes required for neurite outgrowth. Concomitantly, differentiation downregulates expression of S1P2 and S1P5 whose activation would stimulate Rho and inhibit neurite extension. Thus, differential transactivation of S1P receptors by NGF regulates antagonistic signaling pathways during neurite development.