Objective The proapoptotic BH3-only protein Bim is a crucial regulator of neuronal apoptosis.Previous studies have indicated the involvement of the c-Jun, FOXO 1/3a, and B/C-Myb transcription factors in the regulation of Bim during neuronal apoptosis.However, the mechanism underlying the transcriptional regulation of Bim in activity deprivation-induced neuronal apoptosis has remained unclear.The present study is to explore whether is early growth response 1 (Egr-1), rather than c-Jun, FOXO 1/3a, or B/C-Myb, directly transactivates Bim gene expression to mediate apoptosis of rat cerebellar granule neurons.Methods The promoter activities were measured by dual-luciferase reporter assays.The analyses of transcription factors interaction with the promoter were use gel mobility shift assays and chromatin immunoprecipitation assays.Results (1) Egr-1 was sufficient and necessary for neuronal apoptosis.(2) Suppression of Egr-1 activity led to a decrease in Bim expression, whereas overexpression of Egr-1 resulted in induction of Bim.(3) Deletion and site-directed mutagenesis of the Bim promoter revealed that Bim transcriptional activation depends primarily on a putative Egr-binding sequence between nucleotides-56 and-47 upstream of the transcription start site.(4) Egr-1 binding to-56 to-47 upstream of the transcription start site increased in response to activity deprivation in vitro and in vivo.(5) Inhibition of Egr-1 binding to the Bim promoter, by mithramycin A and chromomycin A3, reduced the activity deprivation-induced increases in Bim promoter activity and mRNA and protein levels and protected neurons from apoptosis.(6) Bim overcame the Egr-1 knockdown-mediated inhibition of apoptosis, whereas Bim knockdown impaired the increase in apoptosis induced by Egr-1.Conclusion These findings establish Bim as an Egr-1 target gene in neurons, uncovering a novel Egr-1/Bim pathway by which activity deprivation induces neuronal apoptosis.