Axons extend significant distances to innervate target tissues. At the site of innervation, target tissues release neurotrophins including NGF, BDNF and neurotrophin-3 that stimulate the survival of the associated neuron. Local signaling by activated Trk receptors at the synaptic terminus mediates some presynaptic neuronal responses to neurotrophins. Map kinase pathways activated by Trk receptor activate Erk1 and Erk2 at the terminus stimulating axonal growth, and PI3K activates AKT in the terminus as well. Activation of these kinases does not propagate a signal to the cell body though and does not induce a transcriptional response. This local signaling at the terminus or local signaling at the cell body appears distinct from the signaling pathway that transduces the survival signal from the target tissue. Retrograde axonal transport plays an essential role in neuronal survival induced by neurotrophins released at the target tissue. Failure of retrograde neurotrophin signaling may play a role in neurodegenerative conditions. The neuronal survival signal is initiated by binding of neurotrophins to Trk receptors in the presynaptic membrane, then travels back along the axon to the neuronal cell body. To transmit the signal back along the axon, activated Trk receptors are internalized through receptor-mediated endocytosis and receptor containing vesicles then rapidly travel back to the cell body along axonal microtubules. Several reports indicate that neurotrophins remain receptor-bound during the retrograde axonal transport to the cell body, but recently it was reported that retrograde transport of NGF was not required to induce neuronal survival. Once in the cell body, Trk receptors activate multiple pathways. A key pathway activated by Trk after retrograde transport involves Erk5, also called BMK1. Trk activates Mek5, which activates Erk5, inducing phosphorylation of the CREB and Mef2 transcription factors. Erk5 does not directly phosphorylate CREB, but translocates into the nucleus and phosphorylates the kinase Rsk, which phosphorylates CREB in turn. Both CREB and Mef2 induce a transcriptional program that contributes to neuronal survival. Local activation of Erk5 on the cell body does not appear to induce the same signaling system or neuronal survival, indicating that the retrograde transport is an essential part of the survival signaling system. Also, activation of Erk1 and Erk2 in the cell body can induce CREB activation and neuronal survival, but these kinases are not activated by neurotrophins applied to the axonal terminus. Another pathway activated by retrograde neurotrophin signaling though Erk5 is PI3 Kinase.
