Insulin-like growth factor-I modulation of cerebellar cell populations is developmentally stage-dependent and mediated by specific intracellular pathways.

Although development of transgenic animals overexpressing insulin-like growth factor-I has allowed the establishment of a role of this trophic factor in brain growth, detailed knowledge of the action of insulin-like growth factor-I on different brain areas is still lacking. We now provide evidence for a pleiotrophic role of this growth factor on cerebellar development. Insulin-like growth factor-I produced by cerebellar cultures is a survival factor for Purkinje cells and a mitogen/differentiation factor for cerebellar glioblasts. Trophic effects of insulin-like growth factor-I were observed only during specific developmental stages. In addition, insulin-like growth factor-I increased intracellular Ca2+ levels in Purkinje cells and c-Fos in dividing glioblasts. Survival-promoting effects of insulin-like growth factor-I on Purkinje cells required activation of protein kinase C, while glioblast division induced by insulin-like growth factor-I depended on phosphatidylinosytol 3-kinase activation. We conclude that insulin-like growth factor-I is a paracrine/autocrine pleiotrophic factor for both glia and neurons in the cerebellum. Its effects are mediated by distinct intracellular signals and appear to be specific to the developmental stage of the target cell. Since development of the different cell populations that compose a specific brain territory is not synchronized, the pleiotrophic action of growth factors such as insulin-like growth factor-I may be essential to ontogenetic processes underlying normal brain growth.