NGF utilizes c-Ret via a novel GFL-independent, inter-RTK signaling mechanism to maintain the trophic status of mature sympathetic neurons.

During postnatal development, sympathetic neurons lose their dependence upon NGF for survival but continue to require NGF for soma and process growth and for development of a mature neurotransmitter phenotype. Although c-Ret is expressed in sympathetic neurons during this period, its function in these transitional processes is unclear. The level of Ret phosphorylation markedly increased with postnatal age in SCG neurons in vitro and in vivo. Postnatal Ret phosphorylation did not require either GFLs or GFR(alpha) coreceptors. Instead, NGF promoted age-dependent Ret phosphorylation with delayed kinetics both in vitro and in vivo. Functionally, maximal NGF-dependent trophism of mature sympathetic neurons required Ret, but not GFR(alpha) coreceptors. Therefore, NGF promotes phosphorylation of the heterologous RTK Ret resulting in augmented growth, metabolism, and gene expression.