EGFR activation mediates inhibition of axon regeneration by myelin and chondroitin sulfate proteoglycans (Science, 2005, 310:106-110)

報告日期: 2006/05/19
報告時間: 17:10/18:00
報告學生: 羅振鵬 (英文報告)
講評老師: 郭余民
附件下載:

 http://basicmed.med.ncku.edu.tw/upload_data/950519-3.pdf

 

EGFR activation mediates inhibition of axon regeneration by myelin and chondroitin sulfate proteoglycans

Science, 2005, 310:106-110

Speaker: Lo Chen-Peng                    Room: 602

Commentator: Kuo Yu-Min                 Date: 2006/05/19 17:00~18:00

 

Abstract:

Neuron regeneration is limited in the adult central nervous system (CNS). In previous studies, more evidences suggested that inhibitory molecules in myelin and the glial scar inhibit the axon regeneration, such as myelin-associated glycoprotein (MAG), Nogo-A, oligodendrocyte myelin glycoprotein (OMgp), and chondroitin sulfate proteoglycans (CSPGs). But the detail intracellular mechanisms remained unclear. In this study, the authors screened approximately 400 small molecules in a neurite outgrowth assay and found only the EGFR kinase inhibitors could recover the myelin-induced neurite outgrowth inhibition. The neurite outgrowth of dorsal root ganglion (DRG) cells over expressing wild-type EGFR was inhibited by myelin, while those over expressing kinase deficient EGFR were not. In addition, EGFR could be activated by Nogo-66, OMgp and CSPGs, and the activation was depended on the Nogo receptor (NgR). Calcium chelators EGTA and BAPTA-AM could abolish the Nogo-66-induced EGFR activation. Also, the calcium-independent neurite repulsion by Semaphorin3A was not affected by EGFR truncating nor activation inhibiting. Combing these, EGFR might be a calcium-specific signaling molecule in axon guidance pathways. In the optic nerve crush model, EGFR kinase inhibitor PD168393 treatment increased the number of regenerating axon 0.25 mm beyond the injury site, as compared with control mice. This better outcome was not a result of cell survival improvement. Taken together, EGFR activation might be a critical downstream of the intracellular calcium influx-induced by myelin inhibitors and CSPGs. EGFR inhibitors might be useful for promoting axon regeneration after CNS injury.

 

 

Reference:

1.     Mi S, et al., Nat Neurosci., 2004, (3):221-8.

2.     Silver J, et al., Nat Rev Neurosci., 2004, (2):146-56.