SIGNALING PATHWAYS AND SURVIVAL EFFECTS OF BDNF AND NT-3 ON CULTURED CEREBELLAR GRANULE CELLS

We investigated the signaling pathways exerted by brain-derived neurot rophic factor (BDNF) and neurotrophin-3 (NT-3) in relation to their su rvival-promoting effects on dissociated cultures of cerebellar granule cells prepared from postnatal 9-day-old rats. Granule neuron survival in culture was supported by BDNF, but not significantly by either ner ve growth factor (NGF) or NT-3. BDNF and NT-3 resulted in not only the respective autophosphorylation of the Trk receptors, TrkB or TrkC, bu t also tyrosine phosphorylation of SHC, a protein involved in controll ing p21(ras) activity, and phosphatidylinositol-3' (PI-3') kinase. NGF does not result in TrkA phosphorylation, In parallel, c-Sos was induc ed within 30 min, in response to BDNF and NT-3. NT-3 induced the phosp horylation of these proteins to a lesser extent than BDNF. BDNF also i nduced the tyrosine phosphorylation of phospholipase C gamma (PLC gamm a), but the NT-3-induced one was not detected. We postulate that no su rvival promotion by NT-3 is due to lesser level of trkC expression and of the NT-3-induced signaling in the cultured cerebellar granule neur ons. Wortmannin, a specific inhibitor of PI-3' inhibited the BDNF effe ct on neuronal survival. PI-3' kinase-dependent pathways might be invo lved in the promotion of cerebellar granule cell survival by BDNF.