Many neuronal populations depend upon trophic molecules supplied by the target cells they innervate for survival and growth during development. The prototypical target-derived neurotrophic molecule, nerve growth factor (NGF), is a member of a family of related molecules called the neurotrophins. NGF promotes growth and survival of sympathetic and some populations of sensory neurons. Because NGF is a target-derived factor, it interacts with receptors on the nerve terminal that must transduce a signal retrogradely to influence biochemical events in the cell body. However, the nature of the retrograde signal propagated from the nerve terminal to the cell body is unclear. We have elaborated upon a compartmentalized culture system utilizing sympathetic neurons developed by R. Campenot in which we can stimulate nerve terminals with NGF and subsequently monitor biochemical responses in single neuronal nuclei. Using this system we have been able to demonstrate that NGF applied to nerve terminals induces phosphorylation of the transcription factor CREB on its transcriptional regulatory site, Ser-133. We propose. in three specific aims, to further investigate whether terminally applied NGF activates transcription of genes that are critical for the sympathetic neuron phenotype which NGF receptors present on nerve terminals are necessary for retrograde signaling to occur, and what the retrograde signal is by examining molecular and kinetic aspects of it. A better understanding of how neurotrophins signal in a retrograde fashion could provide important therapeutic insight into neurological disorders involving selective losses of neurotrophin-dependent neurons, such as the basal forebrain cholinergic pathway which rapidly degenerates in Alzheimer's disease, as well as developmental abnormalities that are thought to underlie some psychiatric disorders.
| Tsui-Pierchala, B A; Ginty, D D (1999) Characterization of an NGF-P-TrkA retrograde-signaling complex and age-dependent regulation of TrkA phosphorylation in sympathetic neurons. J Neurosci 19:8207-18 |
