Pancreatic beta cells (insulin-producing cells) and neuronal cells share a large number of similarities. Here, we investigate whether the same mechanisms could control the expression of neuronal genes in both neurons and insulin-producing cells. For that purpose, we tested the role of the transcriptional repressor neuron-restrictive silencing factor/repressor element silencing transciption factor (NRSF/REST) in the expression of a battery of neuronal genes in insulin-producing cells. NRSF/REST is a negative regulator of the neuronal fate. It is known to silence neuronal-specific genes in non-neuronal cells. We demonstrate that, as in the case of the neuronal pheochromocytoma cell line PC12, mRNA coding for NRSF/REST is absent from the insulinoma cell line INS-1 and from three other insulin-and glucagon-producing cell lines. NRSF/REST activity is also absent from insulin-producing cell lines. Transient expression of REST in insulin-producing cell lines is sufficient to silence a reporter gene containing a NRSF/ REST binding site, demonstrating the role of NRSF/ REST in the expression of neuronal markers in insulinproducing cells. Finally, by searching for the expression of NRSF/REST-regulated genes in insulin-producing cells, we increased the list of the genes expressed in both neurons and insulin-producing cells.It is now well established that, in spite of different embryological origins, beta and neuronal cells share a large number of similarities. Indeed, molecules such as glutamic acid decarboxylase (1), tyrosine hydroxylase (2), dopamine -hydroxylase (3), type II voltage-dependent sodium channel (4), glutamate receptor (5), neurofilament proteins (6, 7), receptors for neurotrophins (8, 9), and thyrotropin-releasing hormone (10, 11) have been shown to be expressed in both beta and neuronal cells.The regulation of the expression of neuronal markers in beta cells at the molecular level is not understood. Theoretically, the expression of the same gene in two different cell types can be explained by either the presence in both cell types of specific transcriptional activators or the absence of specific transcriptional repressors. At least three specific transcriptional activators, Islet-1 (12), Pax-6 (13), and Beta2 (14), are expressed in both beta and neuronal cells. To our knowledge, there are no data demonstrating the role of transcriptional repressors in the expression of neuronal molecules by beta cells.Recently, progress has been made on the mechanisms underlying the specific expression of genes in neurons. It has indeed been demonstrated that a large battery of neuron-specific genes was regulated by one silencer protein. This repressor, named NRSF/REST, 1 is present in non-neuronal cells and absent from neuronal cells (15, 16). It was cloned according to its ability to bind a 24-bp cis-element necessary and sufficient for silencing neuron-specific genes such as the type II voltage-dependent sodium channel gene and the SCG10 gene, another neuron-specific gene. This 24-bp cis-element, which represents a bin...