Neural-restrictive silencer (NRS) has been well characterized in SCG10 and many other neuron-specific genes; it is, however, unknown whether the promoters of the SCLIP and RB3 genes (two other SCG10 family members) share basal transcriptional mechanisms with SCG10 or not. To explore how NRS-mediated neural-specific gene transcription has evolved, we determined the genomic and promoter structures of the SCLIP gene, and found that the gene retained an NRS-like element that functioned as a negative regulator in non-neuronal cells. However, unlike the NRS in the SCG10 gene, this NRS(SCLIP) was located downstream of the transcription start site, and showed a position-dependent repressing activity. Further gel-shift and NRS factor (NRSF) co-transfection experiments revealed that NRS(SCLIP) was bound and regulated by NRSF. Such an element was not found in the gene promoter of RB3, suggesting that the NRS-NRSF regulatory system evolved once SCLIP had diverged from RB3 or stathmin.