Activation of phosphatidylinositol 3-kinase, but not extracellular-regulated kinases, is necessary to mediate brain-derived neurotrophic factor-induced motoneuron survival

Chick embryo spinal cord motoneurons develop a trophic response to some neu rotrophins when they are maintained in culture in the presence of muscle ex tract. Thus, after 2 days in culture, brain-derived neurotrophic factor (BD NF) promotes motoneuron survival. In the present study we have analyzed the intracellular pathways that may be involved in the BDNF-induced motoneuron survival. We have observed that BDNF activated the extracellular-regulated kinase (ERK) mitogen-activated protein (MAP) kinase and the phosphatidylin ositol (PI) 3-kinase pathways. To examine the contribution of these pathway s to the survival effect triggered by BDNF, we used PD 98059, a specific in hibitor of MAP kinase kinase, and LY 294002, a selective inhibitor of PI 3- kinase, PD 98059, at doses that significantly reduced the phosphorylation o f ERKs, did not show any prominent effect on neuronal survival, However, LY 294002 at doses that inhibited the phosphorylation of AM, a downstream ele ment of the PI 3-kinase, completely abolished the motoneuron survival effec ts of BDNF, Moreover, cell death triggered by tY 294002 treatment exhibited features similar to those observed after muscle extract deprivation. Our r esults suggest that the PI 3-kinase pathway plays an important role in the survival effect triggered by BDNF on motoneurons, whereas activation of the ERK MAP kinase pathway is not relevant.