Long projection axons regenerate poorly through the damaged central nervous system. One key reason is the environment through which they must re-grow contains many biochemical signals that trigger signaling pathways which inhibit axon outgrowth. Some of these inhibitory cues are repellents that play an important role in guiding axons to their appropriate targets during normal embryonic development. Our previous work has shown that activation of a specific G-protien coupled signaling pathway, for example by the chemokine SDF1 activating its receptor CXCR4, makes axons less responsive to several different repellent guidance cues. We have partially characterized this anti-repellent signaling pathway with pharmacological reagents in tissue culture experiments and with anti-sense reagents in zebrafish embryogenesis.
The aims of this project are: to characterize several additional signaling steps in the pathway, to identify dominant-negative proteins that can block steps in the pathway both in culture and in the embryo, and to examine how this anti-repellent signaling pathway affects sensory axon guidance during normal development. A better understanding of this pathway will further our understanding of how multiple guidance cues are integrated into single decisions by growing axons during normal development and will likely suggest novel approaches to promoting regeneration in the mature central nervous system.PROJECT NARRATIVE Spinal cord injuries leave approximately 10,000 people partially or fully paralyzed in the United States each year. The prognosis for these kinds of injuries is extremely poor since damaged neurons are unable to re-grow long axonal processes in the central nervous system. This project discovered and is now characterizing a signaling pathway that makes axons resistant to repellent guidance cues like those that prevent axonal regeneration.
|Dell, Alison L; Fried-Cassorla, Emma; Xu, Hong et al. (2013) cAMP-induced expression of neuropilin1 promotes retinal axon crossing in the zebrafish optic chiasm. J Neurosci 33:11076-88|
|Lakhina, Vanisha; Marcaccio, Christina L; Shao, Xin et al. (2012) Netrin/DCC signaling guides olfactory sensory axons to their correct location in the olfactory bulb. J Neurosci 32:4440-56|
|Twery, E Naomi; Raper, Jonathan A (2011) SDF1-induced antagonism of axonal repulsion requires multiple G-protein coupled signaling components that work in parallel. PLoS One 6:e18896|
|Xu, Hong; Leinwand, Sarah G; Dell, Alison L et al. (2010) The calmodulin-stimulated adenylate cyclase ADCY8 sets the sensitivity of zebrafish retinal axons to midline repellents and is required for normal midline crossing. J Neurosci 30:7423-33|