Bringing It All Back

Abstract

Two studies suggest that the endocytosis and retrograde transport of endosomal nerve growth factor (NGF) and TrkA, its receptor tyrosine kinase, are required for NGF-mediated neuronal survival. Target-derived growth factors, such as NGF, are critical for the survival of peripheral neurons. In sympathetic and sensory neurons, NGF-mediated survival depends on a retrograde signal from the nerve terminal to the cell body. The precise nature of this signal--which, in humans, may travel a meter or more--and whether survival requires the endocytosis and retrograde transport of NGF or TrkA has been debated for many years (see Preview by Chao). Ye et al. grew sympathetic neurons in compartmentalized cultures and applied various agents (including NGF, a TrkA inhibitor, and a neutralizing antibody to NGF) to different neuronal regions. Survival depended on TrkA kinase activity in both the cell body and distal axon and on available NGF in the cell body, but was independent of TrkA activity in the proximal axon. Endocytosis was required for survival when NGF was applied to the distal axon but not the cell body. Delcroix et al. investigated retrograde transport of NGF and NGF-stimulated retrograde transport and activation of TrkA and downstream signaling molecules in rat sensory neurons in vivo and in isolated segments of sciatic nerve in vitro. The authors used microscopy, analysis of different nerve regions, and density-gradient fractionation to show that these proteins were associated with each other and with endosomal markers and were found in endosomal fractions. Together, these studies support a "signaling endosome" model in which endosomal transport of NGF and TrkA, together with various effectors, are required for the retrograde survival signal. H. Ye, R. Kuruvilla, L. S. Zweifel, D. D. Ginty, Evidence in support of signaling endosome-based retrograde survival of sympathetic neurons. Neuron 39 , 57-68 (2003). [Online Journal] J.-D. Delcroix, J. S. Valetta, C. Wu, S. J. Hunt, A. S. Kowal, W. C. Mobley, NGF signaling in sensory neurons: Evidence that early endosomes carry NGF retrograde signals. Neuron 38 , 69-84 (2003). [Online Journal] M. V. Chao, Retrograde transport redux, Neuron 38 , 1-2 (2003). [Online Journal]