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Published on: May 3, 2017
Epidermal growth factor receptor antagonists and CNS axon regeneration: mechanisms and controversies
Martin Berry1, Zubair Ahmed, Michael R Douglas
1Molecular Neuroscience Group, Neuropharmacology and Neurobiology Section, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, UK.
Abstract:
The reasons for the failure of central nervous system (CNS) axons to regenerate include the presence of myelin- and non-myelin derived inhibitory molecules, neuronal apoptosis and the absence of a potent neurotrophic stimulus. Transactivation of the epidermal growth factor receptor (EGFR) has been implicated in signalling inhibition of axon growth in the CNS. Small molecule EGFR inhibitors such as AG1478 and PD168393 promote CNS axon growth after optic nerve transection despite the presence of inhibitory molecules in the environment of the regenerating axon. However, our results demonstrate that phosphorylated EGFR (pEGFR) is not present on regenerating axons and that the majority of pEGFR is present in glia, suggesting that EGFR cannot play a direct intra-axonal role in signalling inhibition and thus disinhibited CNS axon growth must be indirectly mediated by glia. We argue that EGFR may not have a role in signalling axon growth inhibition since AG1478 and PD168393 promotes neuronal neurite outgrowth in CNS myelin-inhibited cultures after EGFR knockdown. This review discusses the current evidences for and against the involvement of EGFR in signalling myelin inhibition.
Insights
Epidermal growth factor receptor (EGFR) inhibitors promote central nervous system (CNS) axon growth by indirectly affecting glia, not directly inhibiting neurons. This suggests a glial-mediated mechanism for disinhibited CNS axon regeneration.
Area of Science:
- Neuroscience
- Cell Biology
- Regenerative Medicine
Background:
- Central nervous system (CNS) axon regeneration is hindered by inhibitory molecules, neuronal apoptosis, and lack of neurotrophic support.
- Transactivation of epidermal growth factor receptor (EGFR) is proposed to mediate signaling inhibition of CNS axon growth.
Purpose of the Study:
- To investigate the direct role of EGFR in signaling inhibition of CNS axon growth.
- To clarify the mechanism by which EGFR inhibitors promote CNS axon regeneration.
Main Methods:
- Utilized small molecule EGFR inhibitors (AG1478, PD168393) in optic nerve transection models.
- Examined the localization of phosphorylated EGFR (pEGFR) in regenerating axons and surrounding glia.
- Assessed the effect of EGFR knockdown on neuronal neurite outgrowth in myelin-inhibited cultures.
Main Results:
- Phosphorylated EGFR (pEGFR) was primarily found in glia, not on regenerating axons.
- EGFR inhibitors promoted CNS axon growth, suggesting an indirect, glial-mediated mechanism.
- EGFR knockdown did not prevent EGFR inhibitors from promoting neurite outgrowth in myelin-inhibited cultures.
Conclusions:
- EGFR does not appear to directly inhibit CNS axon growth within neurons.
- EGFR-mediated signaling inhibition of axon growth is likely indirectly mediated by glia.
- The precise role of EGFR in myelin-induced growth inhibition requires further investigation.
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