Fast electrical signaling in the nervous system is mediated by action potentials. The type II Na channel often is responsible for the generation of action potentials in the mammalian central nervous system. The 5' flanking sequence of the type II gene has been cloned and characterized. The presence of a 28-bp DNA element in the regulatory region is required for restricting the expression of type II reporter genes to neuronal cells (PC12). The transcription factor (REST) that binds to this silencer element in the type II gene and mediates its neuron-specific expression has been identified. In cell lines and mouse embryos, REST ist detected only in cell types that fail to express this sodium channel gene. Furthermore, cotransfection assays of PC12 cells with type II reporter genes and a recombinant REST cDNA results in silencing of the type II promoter. We propose that expression of this sodium channel reflects a 'default' pathway in neurons which is blocked by the presence of REST in nonneuronal cells and perhaps in some cells in the adult peripheral nervous system. A rapidly increasing number of genes containing an RE1-like sequence has been reported (SCG10, synapsin, Ng-CAM and DBH) suggesting that a similar silencing mechanism underlies neuron-specific expression of these genes.