Spatial requirements for TrkA kinase activity in the support of neuronal survival and axon growth in rat sympathetic neurons

Abstract

Nerve growth factor (NGF) interacts with its receptor tyrosine kinase, TrkA, at axon terminals to produce local signals within axon terminals and retrograde signals to the neuronal cell body. According to prevalent theory, retrograde signaling requires the retrograde transport to the cell bodies of signaling endosomes containing activated TrkA complexed with NGF. Alternative mechanisms in which retrograde signals reach the cell bodies unaccompanied by NGF may or may not require activated TrkA in the cell body. To help distinguish this possibility, we investigated the spatial requirements of TrkA kinase activity for neuronal survival and axon growth in rat sympathetic neurons supported by NGF provided only to distal axons. Inhibition of local TrkA kinase activity in the distal axons by K252a blocked local axon growth and induced apoptosis. Although local application of K252a to cell bodies/proximal axons resulted in a sustained loss of phosphorylated TrkA from the cell bodies/proximal axons, the neurons survived, and growth of the distal axons was not inhibited. These results suggest that TrkA kinase activity in distal axons, but not in the cell bodies, is required for both local growth and retrograde survival signaling. These results support the hypothesis that retrograde signals can be carried by mechanisms downstream of TrkA activity.