Transcriptional Elements Active in Developmental and Regenerative Axon Growth

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DESCRIPTION (provided by applicant): Development and regeneration of the vertebrate nervous system are dependent on the capacity of neurons to extend axons that will forge functional connections with the appropriate postsynaptic targets. While there are many similarities between axon growth during development and regeneration, it has been shown that some requirements for axon growth during regeneration are distinct from those involved in developmental axon growth. The goal of this research is to identify gene regulatory elements that respond to signaling pathways regulating axon growth in the regenerating nervous system. Genes encoding neuronal growth- associated proteins (nGAPs) are likely targets of axon growth regulatory pathways given the tight correlation between nGAP gene expression and periods of axon growth. A prototypical nGAP is GAP-43, a membrane- associated protein that is enriched in axonal growth cones and is active in axon growth and guidance. Like other nGAPs, GAP-43 is expressed maximally in newly differentiated neurons undergoing initial axon growth and remodeling, and is subsequently down regulated in the mature nervous system where axon growth activity is minimal. Expression of GAP-43 can be reactivated in the mature nervous system in response to injury in those neurons capable of regeneration. The signaling pathways that mediate the transcriptional activation and repression of nGAP genes are largely unknown. The studies proposed herein will use a functional comparative genomics approach in zebrafish to dissect out specific transcriptional regulatory elements within the GAP-43 gene that are responsible for regulating gene expression during nervous system development, maturation and regeneration. Understanding how nGAP genes are regulated is an important step to determining how their expression can be turned on and sustained in damaged neurons in order to induce regenerative axon growth in neurons that normally do not display a capacity for regeneration.