Differential activation of phospholipases by mitogenic EGF and neurogenic PDGF in immortalized hippocampal stem cell lines

In several neuronal systems, nerve growth factor (NGF) and plate let-derive d growth factor (PDGF) act as neurogenic agents, whereas epidermal growth f actor (EGF) acts as a mitogenic agent. Hippocampal stem cell lines (HiB5) i mmortalized by the expression of a temperature-sensitive SV40 large T antig en also respond differentially to EGF and PDGF. While EGF treatment at the permissive temperature induces proliferation, the addition of PDGF induces differentiation at the non-permissive temperature. However, the mechanism r esponsible for these different cellular fates has not been clearly elucidat ed. In order to clarify possible critical signaling events leading to these distinct cellular outcomes, we examined whether either EGF or PDGF differe ntially induces the activation of phospholipases, such as phospholipase A(2 ) (PLA(2)), C (PLC), or D (PLD). Although EGF stimulation did not induce ph ospholipases, PDGF caused a rapid and transient activation of PLC and PLD, but not PLA(2). When the activation of PLC or PLD was blocked, the neurite outgrowth induced by PDGF was significantly inhibited. Although the activat ion of PLD occurred faster than PLC, blocking of PLD activity by transient expression of lipase-inactive mutants did not inhibit the induction of PLC activity by PDGF. These results suggest that the differential activation of phospholipases may play an important role in signal transduction by mitoge nic EGF and neurotrophic PDGF in HiB5 neuronal hippocampal stem cells. In p articular, the activation of phospholipase C and D may contribute to neuron al differentiation by neurogenic PDGF in the HiB5 cells.