Axoplasmic importins enable retrograde injury signaling in lesioned nerve.
Axoplasmic proteins containing nuclear localization signals (NLS) signal retrogradely by an unknown mechanism in injured nerve. Here we demonstrate that the importin/karyopherin alpha and beta families underlie this process. We show that importins are found in axons at significant distances from the cell body and that importin beta protein is increased after nerve lesion by local translation of axonal mRNA. This leads to formation of a high-affinity NLS binding complex that traffics retrogradely with the motor protein dynein. Trituration of synthetic NLS peptide at the injury site of axotomized dorsal root ganglion (DRG) neurons delays their regenerative outgrowth, and NLS introduction to sciatic nerve concomitantly with a crush injury suppresses the conditioning lesion induced transition from arborizing to elongating growth in L4/L5 DRG neurons. These data suggest a model whereby lesion-induced upregulation of axonal importin beta may enable retrograde transport of signals that modulate the regeneration of injured neurons.
Hanz
Shlomit
S
Molecular Neurobiology Group, Department of Biological Chemistry, Weizmann Institute of Science, 76100, Rehovot, Israel.
Perlson
Eran
E
Willis
Dianna
D
Zheng
Jun-Qi
JQ
Massarwa
R'ada
R
Huerta
Juan J
JJ
Koltzenburg
Martin
M
Kohler
Matthias
M
van-Minnen
Jan
J
Twiss
Jeffery L
JL
Fainzilber
Mike
M
D000818:Animals; D001370:Axonal Transport / Q000502:physiology*; D002478:Cells, Cultured; D006801:Humans; D028884:Karyopherins / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012183:Retrograde Degeneration / Q000235:genetics / Q000378:metabolism*; D020426:Sciatic Neuropathy / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology
D028884:Karyopherins; D012333:RNA, Messenger