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 troph ic factor in brain growth, detailed knowledge of the action of insulin -like growth factor-I on different brain areas is still lacking. We no w provide evidence for a pleiotrophic role of this growth factor on ce rebellar development. Insulin-like growth factor-I produced by cerebel lar cultures is a survival factor for Purkinje cells and a mitogen/dif ferentiation factor for cerebellar glioblasts. Trophic effects of insu lin-like growth factor-I were observed only during specific developmen tal stages. In addition, insulin-like growth factor-I increased intrac ellular Ca2+ levels in Purkinje cells and c-Fos in dividing glioblasts . Survival-promoting effects of insulin-like growth factor-I on Purkin je cells required activation of protein kinase C, while glioblast divi sion induced by insulin-like growth factor-I depended on phosphatidyli nosytol 3-kinase activation. We conclude that insulin-like growth fact or-I is a paracrine/autocrine pleiotrophic factor for both glia and ne urons in the cerebellum. Its effects are mediated by distinct intracel lular signals and appear to be specific to the developmental stage of the target cell. Since development of the different cell populations t hat compose a specific brain territory is not synchronized, the pleiot rophic action of growth factors such as insulin-like growth factor-I m ay be essential to ontogenetic processes underlying normal brain growt h. (C) 1997 IBRO. Published by Elsevier Science Ltd.