SPATIAL REGULATION OF NEURONAL GENE-EXPRESSION IN RESPONSE TO NERVE GROWTH-FACTOR

To examine the cellular mechanisms whereby distally derived growth fac tors regulate nuclear responses in neurons, we have utilized compartme nted cultures of sympathetic neurons to examine the regulation of two nerve growth factor (NGF)-inducible genes, tyrosine hydroxylase (TH) a nd p75 neurotrophin receptor (p75NTR). These studies demonstrate that NGF can signal retrogradely to mediate the induction of TH and p75NTR mRNAs. However, quantitative differences occurred as a function of the spatial localization of NGF exposure; application of NGF to cell bodi es and proximal axons elicited peak levels of neuronal gene expression that were two- to threefold higher than when NGF was applied to dista l axons alone. Furthermore, neurons responding maximally to NGF on dis tal axons were still able to respond to NGF administered to cell bodie s and proximal axons. Biochemical analysis indicated that this differe nce in responsiveness was not due to differences in the number of TrkA /NGF receptors in the two compartments. Thus, although NGF signals ret rogradely to mediate nuclear responses, the magnitude of these respons es differs as a function of the spatial location of the activated NGF receptor:ligand complex. Moreover, these data suggest that neurons may be able to respond to a second cellular source of neurotrophins, even when target-derived neurotrophins are not limiting. (C) 1997 Academic Press.