A semaphorin 3A inhibitor blocks axonal chemorepulsion and enhances axon regeneration.
Secreted semaphorins are a large group of extracellular proteins involved in a variety of processes during development, including neuronal migration and axon guidance. We screened a peptoid combinatorial library to search for semaphorin 3A inhibitors, and identified a peptoid (SICHI: semaphorin Induced chemorepulsion inhibitor) that blocks semaphorin 3A-chemorepulsion and growth-cone collapse in axons at millimolar concentrations. SICHI inhibits the binding of semaphorin 3A to its receptor complex (neuropilin 1/plexin A1) and semaphorin 3A-induced phosphorylation of GSK3. Chemorepulsion induced by semaphorin 3F or netrin 1 is not blocked by SICHI. We also show that SICHI promotes neural regeneration of damaged axons. We suggest that SICHI, a selective inhibitor of semaphorin 3A, is of therapeutic interest for approaches aimed at promoting axonal regeneration and brain repair.
Montolio
Marisol
M
IRB Barcelona, Department of Cell Biology, University of Barcelona, and CIBERNED (ISCIII), Barcelona Science Park, Baldiri i Reixac 10, Barcelona E-08028, Spain.
Messeguer
Joaquim
J
Masip
Isabel
I
Guijarro
Patricia
P
Gavin
Rosalina
R
Antonio Del Río
José
J
Messeguer
Angel
A
Soriano
Eduardo
E
D000818:Animals; D001369:Axons / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D020439:Growth Cones; D051379:Mice; D009414:Nerve Growth Factors; D009416:Nerve Regeneration; D000075388:Netrin-1; D019151:Peptide Library; D010766:Phosphorylation; D012038:Regeneration; D040121:Semaphorin-3A / Q000037:antagonists & inhibitors*; D025521:Tumor Suppressor Proteins
D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; D019151:Peptide Library; D040121:Semaphorin-3A; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1; D038362:Glycogen Synthase Kinase 3