Interferons and IRF-1 induce expression of the survival motor neuron (SMN)genes

Background: Spinal muscular atrophy (SMA) is a common recessive disorder, c haracterized by degeneration of motor neurons of the spinal cord. Deletions , conversions, or mutations of the survival motor neuron gene (SMN) are res ponsible for SMA. A highly homologous centromeric copy of the SMN gene (SMN c) remains intact in SMA patients. However, the-re is an inverse correlatio n between the amount of the SMNc gene product and the clinical severity of the disease. An understanding of SMN and SMNc gene regulation is, therefore , an important step towards therapy for SMA. Results: We identified a candidate Interferon-stimulated Response Element ( ISRE), overlapping with an Interferon Regulatory Factors binding motif (IRF -E) in the promoter region of SMN and SMNc genes. Both ISRE and IRF-E motif s are involved in mediating transcriptional induction of interferon-stimula ted gene expression. We, therefore, investigated whether SMN and SMNc genes were regulated by interferons (IFN). Here we show that both IFN-beta and I FN-gamma rapidly induced SMN and SMNc mRNA and protein expression in variou s cell lines. The transcription factor IRF-1 bound to the candidate ISRE/IR F-E sequence of SMN and SMNc genes in vitro and overexpression of IRF-1 ind uced expression of both genes in transfection assays. IRF-1 is, therefore, at least in part responsible for the induction of SMN and SMNc by IFNs. In primary culture of fibroblasts from SMA patients, IFN-beta and IFN-gamma in duced SMNc gene expression and restored protein defect.