Diabetes is the most prevalent and serious metabolic disease, and the number of diabetic patients worldwide is increasing. The reduction of insulin biosynthes is in pancreatic β-cells is closely associated with the onset and progression of diabetes, therefore, it is important to search for ways to induce insulin-producing cells in non-β-cells. In the present study, it has been reported that activin A and a basic fibroblast growth factor 2 ( FGF2), can synergistically increase the insulin mRNA level, in both mouse E14 striatal primary cell cultures and the hippocampal neuronal cell line HT22. Activin A and FGF2 can jointly stimulate the nuclear translocation of Smad3 and specifically activate ERK1/2. It is interesting to note that a specific inhibitor for MEK, U0126, can efficiently block the induction of an insulin promoter activity by activin A and FGF2. This indicates that activin A collaborates with FGF2, giving a signal to induce the insulin gene through selective activation of the ERK-type MAP kinase and Smad3 in mouse striatal and HT22 cells. These data suggest that activin A may act in concert with FGF2 for the development of insulin -positive neurons.