A nerve growth factor-induced retrograde survival signal mediated by mechanisms downstream of TrkA

Considerable evidence suggests that mammalian neurons are always poised to destroy themselves by apoptosis but are blocked by retrograde survival signals triggered in their axon terminals by neurotrophic factors secreted by the target cells they innervate. Studies with nerve growth factor (NGF) and its receptor, TrkA, form the basis of the prevalent theory of retrograde signaling. According to this theory, retrograde survival signals travel to the cell bodies in the form of endosomes produced at the axon terminals with internalized NGF in their lumens bound to phosphorylated TrkA in their membranes. The inhibition of TrkA phosphorylation in the cell bodies of sympathetic neurons in compartmented cultures by K252a blocked retrograde NGF signaling in some studies in accord with this theory, but other studies do not show a block. We report that local block of TrkA phosphorylation in the cell bodies and proximal axons with another kinase inhibitor, Gö6976 (25 nM), did not block the survival signal from NGF at distal axons, while Gö6976 at the distal axons completely blocked the retrograde survival signal. These results suggest that downstream signals activated by phosphorylated TrkA in the distal axons carry the retrograde survival signals to the cell bodies, possibly via a downstream type of signaling endosome not necessarily transporting NGF or phosphorylated TrkA. Unlike Gö6976, K252a exerted a survival effect on its own when applied to cell bodies/proximal axons or distal axons of completely NGF-deprived neurons. The latter effect suggests that downstream retrograde survival signals can arise from alterations in one or more kinase activities in the distal axons without activation of TrkA by NGF.