| Abstract No.: | C-A3018 |
| Country: | Canada |
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| Title: | MOLECULAR MECHANISM OF RETINAL AXON GUIDANCE BY SONIC HEDGEHOG |
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| Authors/Affiliations: | 1 Pierre Fabre*; 1 Martin Levesque; 1 Frédéric Charron;
1 IRCM, Montréal, QC, Canada
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| Content: | Objectives: Axon guidance is a developmental process that is essential for the wiring of the nervous system. Sonic Hedgehog (Shh) is a secreted protein which attracts commissural axons and repels retinal ganglion cell (RGC) axons. We have identified two new receptors (Boc and Cdon) for Shh and one of them, Boc, is required for commissural axon attraction by Shh. However, the role of these new receptors in RGC axon guidance is still unknown.
Materials and Methods: Using reporter gene expression and immunohistochemistry, we analyzed the expression pattern at the RNA and protein level for Boc and Cdon during development of RGC axonal projections. Using time-lapse microscopy, we also established an in vitro functional assay to analyze the repulsive effect of Shh on RGC axons. Finally, we performed DiI labeling of the mouse retina to study the trajectories of RGC in Boc and Cdon mutant mice in vivo. Results: Boc and Cdon are expressed during development of RGC axonal projections; only a subpopulation of RGC express Boc while most of the RGC express Cdon. At the protein level, Boc and Cdon localize in the soma and the axon of these neurons, suggesting that these new receptors could have a role in the guidance of RGC axons. Using a real time imaging assay with retinal explants from Boc mutant mice, we showed that these neurons are not able to retract after addition of Shh. Finally, preliminary in vivo DiI analysis revealed that retinal axons of Boc mutant mice are misrouted at the chiasmatic level, an area known to express Shh during RGC development. Conclusion: We show that Boc is required for the Shh-induced retraction of retinal cells in vitro. Additionally, our preliminary results suggest that Boc is required in vivo for proper crossing at the optic chiasm level. Taken together, these results suggest that the repulsive effect of Shh on retinal axons is mediated by Boc. This work will help to identify novel strategies to promote the proper rewiring into neural circuits of regenerating axons damaged by neurodegenerative diseases, stroke or brain and spinal cord injuries.
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