|This laboratory is concerned with the regulation of axon growth in developing brains, and the restriction of axon growth in the brain and spinal cord. One consequence of this growth restriction is the failure of axons to regenerate in cases of spinal cord injury, stroke or neurodegenerative diseases. We have found that genes for specific components of axonal "growth cones" are activated during the differentiation of neurons, but repressed during normal maturation. These growth-associated genes are re-induced in cases of successful nerve regeneration, but not after many lesions in the adult brain or spinal cord. One major effort in this lab is to determine which of the "missing" genes are required to trigger regeneration of axons in the adult CNS. Using short-term cultures of adult neurons, we have shown that different sets of neuronal genes are required for distinct modes of axon growth, and that genes induced by peripheral nerve injury are required to trigger the "elongating" mode of axon extension needed for nerve regeneration. Using transgenic mouse models, we then showed that replacement of just two of the genes induced by peripheral nerve injury is sufficient to elicit this type of regenerative growth. Current efforts are testing whether this limited gene replacement can support significant regrowth of axons after spinal cord injury in vivo. A second research focus concerns the molecular signals used to suppress growth associated genes during normal development, and to re-activate these genes after axon injury in adults. By using specific DNA sequences from a mammalian GAP-43 gene to direct expression of a fluorescent reporter gene (EGFP) in transgenic zebrafish, we have shown that the signaling pathways used to suppress growth-associated genes in the mature CNS are very highly conserved. Mutational analysis has been used to identify specific DNA elements involved in this developmental regulation. Expression of the fluorescent GFP in our transgenic zebrafish lines can now be used in genetic screens for genes involved in the signaling pathways responsible for the suppression of axon growth in adult CNS neurons.