Signals that regulate gene transcription during nerve regeneration The successful regeneration of an axon to its target after injury requires alterations in the transcriptional programs that regulate survival, growth, and electrical properties. These alterations are initiated by extrinsic factors released as a result of tissue damage and stress and by intrinsic signaling cascades that communicate between the site of injury and the nucleus. Among the latter are protein kinases that are retrogradely transported from the injury site to the nucleus where they phosphorylate transcription factors. These kinases comprise a subclass of "positive injury signals" and the long term goal of our research is to determine how these signals contribute to regeneration after injury. Our short-term goal is to identify the kinases responsible for inducing the hyperexcitability that occurs after injury. Achieving this goal is important clinically because persistent excitability is a cause of chronic neuropathic pain. We use as our model the cluster of sensory neurons present in the nervous system of Aplysia californica. Like mammalian nociceptors, these neurons mediate responses to noxious stimuli. Their axons enter peripheral nerves that innervate the body wall. The nerves can be removed and axoplasm extruded from their axons, which confers a unique advantage for studies of intrinsic injury signals. We recently identified a unique protein kinase, IAK-1, in axoplasm that is activated by injury and which is transported back to the cell body and into the nucleus. We found that IAK-1 phosphorylates the transcription factor c/EBP, which is associated with regeneration in other cell types. A partial characterization of IAK-w indicated that it is a member of the MAPK family and when we injected a recombinant MAPK into the sensory neurons they became hyperexcitable. Having found a link between IAK-1 and hyperexcitability, we are now extending these studies to see if a similar kinase is activated in rats after sciatic nerve damage and in painful human neuromas. Several kinases in addition to IAK-1 are activated by injury and each phosphorylates a transcription factor. Thus, it appears that many of the changes that occur after injury are mediated by such kinases. The challenge now will be to determine how these kinases are activated, to identify the events they control, and to see whether they have counterparts in human neuropathies.
- Walters, E.T., Ambron, R.T. (1995). Long-term alterations induced by injury and by 5-HT in Aplysia sensory neurons: convergent pathways and common signals? Trends Neurosci. 18: 137-142.
- Ambron, R.T., Dulin, M.F., Zhang, X.-P., Schmied, R., Walters, E.T. (1995). Axoplasm enriched in a protein mobilized by nerve injury induces memory-like alterations in Aplysia neurons. J. Neurosci., 15: 3440-3446.
- Ambron R.T., Walters, E.T. (1996). Priming events and retrograde injury signals: a new perspective on the cellular and molecular biology of nerve regeneration. Mol. Neurobiol., 13: 61-79.
- Ambron , R.T., Zhang, X.-P., Gunstream, J.D., Povelones, M., and Walters, E.T. (1996). Intrinsic injury signals enhance growth, survival, and excitability of Aplysia neurons. J. Neurosci., 16: 7469-7477.
- Povelones, M., Tran, K., Thanos, D., Ambron, R.T. (1997). An NF-kB-like transcription factor in axoplasm is rapidly inactivated after nerve injury in Aplysia. J. Neurosci., 17: 4915-4920.
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