EGFR activation mediates inhibition of axon regeneration by myelin and chondroitin sulfate proteoglycans.
Inhibitory molecules associated with myelin and the glial scar limit axon regeneration in the adult central nervous system (CNS), but the underlying signaling mechanisms of regeneration inhibition are not fully understood. Here, we show that suppressing the kinase function of the epidermal growth factor receptor (EGFR) blocks the activities of both myelin inhibitors and chondroitin sulfate proteoglycans in inhibiting neurite outgrowth. In addition, regeneration inhibitors trigger the phosphorylation of EGFR in a calcium-dependent manner. Local administration of EGFR inhibitors promotes significant regeneration of injured optic nerve fibers, pointing to a promising therapeutic avenue for enhancing axon regeneration after CNS injury.
Koprivica
Vuk
V
Division of Neuroscience, Children's Hospital, Boston, MA 02115, USA.
Cho
Kin-Sang
KS
Park
Jong Bae
JB
Yiu
Glenn
G
Atwal
Jasvinder
J
Gore
Bryan
B
Kim
Jieun A
JA
Lin
Estelle
E
Tessier-Lavigne
Marc
M
Chen
Dong Feng
DF
He
Zhigang
Z
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D058851:GPI-Linked Proteins; D006801:Humans; D051379:Mice; D009185:Myelin Proteins / Q000378:metabolism* / Q000494:pharmacology; D009409:Nerve Crush; D009416:Nerve Regeneration / Q000187:drug effects; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D000070798:Nogo Proteins; D000070816:Nogo Receptor 1; D009900:Optic Nerve / Q000187:drug effects / Q000502:physiology; D020221:Optic Nerve Injuries / Q000188:drug therapy; D010766:Phosphorylation; D011799:Quinazolines / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology
D011508:Chondroitin Sulfate Proteoglycans; D004791:Enzyme Inhibitors; D058851:GPI-Linked Proteins; D009185:Myelin Proteins; D000070798:Nogo Proteins; D000070816:Nogo Receptor 1; D011799:Quinazolines; C000603199:RTN4 protein, human; D011956:Receptors, Cell Surface; C000603201:Rtn4 protein, mouse; C419790:Rtn4r protein, mouse; D020032:Tyrphostins; C101044:RTKI cpd; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D002118:Calcium