Ras/p38 and PI3K/Akt but not Mek/Erk signaling mediate BDNF-induced neurite formation on neonatal cochlear spiral ganglion explants.

Neurotrophins participate in regulating the survival, differentiation, and target innervation of many neurons, mediated by high-affinity Trk and low-affinity p75 receptors. In the cochlea, spiral ganglion (SG) neuron survival is strongly dependent upon neurotrophic input, including brain-derived neurotrophic factor (BDNF), which increases the number of neurite outgrowth in neonatal rat SG in vitro. Less is known about signal transduction pathways linking the activation of neurotrophin receptors to SG neuron nuclei. In particular, the p38 and cJUN Kinase (JNK), mitogen-activated protein kinase (MAPK) pathways, which participate in JNK signaling in other neurons, have not been studied. We found that inhibition of Ras, p38, phosphatidyl inositol 3 kinase (PI3K) or Akt signaling reduced or eliminated BDNF mediated increase in number of neurite outgrowth, while inhibition of Mek/Erk had no influence. Inhibition of Rac/cdc42, which lies upstream of JNK, modestly enhanced BDNF induced formation of neurites. Western blotting implicated p38 and Akt signaling, but not Mek/Erk. The results suggest that the Ras/p38 and PI3K/Akt are the primary pathways by which BDNF promotes its effects. Activation of Rac/cdc42/JNK signaling by BDNF may reduce the formation of neurites. This is in contrast to our previous results on NT-3, in which Mek/Erk signaling was the primary mediator of SG neurite outgrowth in vitro. Our data on BDNF agree with prior results from others that have implicated PI3K/Akt involvement in mediating the effects of BDNF on SG neurons in vitro, including neuronal survival and neurite extension. However, the identification of p38 and JNK involvement is entirely novel. The results suggest that neurotrophins can exert opposing effects on SG neurons, the balance of competing signals influencing the generation of neurites. This competition could provide a potential mechanism for the control of neurite number during development.