The epidermal growth factor receptor inhibitor gefitinib enhances in vitro and in vivo sensory axon regeneration and functional recovery following transection in a mouse median nerve injury model

Authors
Maxwell Topley, Payton Sparks, Anne-Marie Crotty, Michael Kawaja, J. Michael Hendry


Lab

Journal
Muscle & Nerve

Abstract
The implication of EGFR as a negative regulator of sensory nerve regeneration is among the most plausible explanations for the pro-regenerative effects of gefitinib and possibly relates to the CSPG signaling axis. CSPGs are large sulfated proteoglycans that are a major constituent of the regenerative milieu and long recognized as one of the dominant inhibitory cues that impair central and peripheral neuronal elongation.52-54In addition to allosteric interference, their mechanism has recently been shown to function through activation of the protein tyrosine phosphatases LAR and PTPσ.55,56PTPσ exerts an inhibitory influence on both peripheral sensory and motor neurons and is known to inhibit TrkA receptor activation in the presence of nerve growth factor.57-59Impairment in PTPσ signaling via transgenic knockout or inhibition improves compound muscle action potential and sciatic function index following rat sciatic nerve injury, recovery of facial nerve motor function following crush injury and sympathetic axon regeneration.60-62Curiously, the LAR receptor appears to have an opposite function. LAR knockout mice in peripheral nerve injury have diminished sensory nerve recovery, diminished neurite outgrowth, decreased axonal diameter and decreased pinch response.63,64Expression of the LAR receptor is highly regulated post injury and its heterodimer formation with EGFR triggers proteolytic cleavage and downregulation of the LAR receptor.65,66Importantly, LAR in the peripheral nervous system appears only to be expressed in DRG neurons, and not in motor neurons.67The combination of LAR's DRG specific expression and pro-regenerative effect which is suppressed by EGFR signaling could account for our observed sensory neuron specific release from the growth inhibitory effects of CSPG when EGFR is inhibited by gefitinib.

Keywords/Topics
epidermal growth factor receptor; median nerve; nerve regeneration; peripheral nerve injury; peripheral nerve repair

BIOSEB Instruments Used:
Grip strength test (BIO-GS4)

Source :

https://onlinelibrary.wiley.com/doi/abs/10.1002/mus.28291

Produits associés

Test d'agrippement

DEMANDE DE PUBLICATION

Merci de votre intérêt pour notre gamme de produits et de votre demande pour cette publication qui vous sera envoyée si l'équipe de recherche et la revue le permettent. Notre équipe commerciale vous contactera dans les plus brefs délais.