Integrin Activation: Implications for Axon Regeneration
Abstract
:1. Introduction
2. The Challenging Task of Axon Regeneration
3. Integrin Heterodimers as a Transmembrane Signalling Molecule
4. ‘Inside–Out’ Signalling
4.1. Kindlin
4.2. Talin
4.3. Intracellular Interactions with Kindlin and Talin
- (1)
- The sequential binding model: Kindlin binds to the membrane-distal NxxY motif to induce a slight change in the conformation of the β subunit cytoplasmic tail and this facilitates the binding of talin to the membrane-proximal NPxY motif.
- (2)
- The Cis co-operation model: Simultaneous binding of kindlin and talin to the same β subunit integrin cytoplasmic tail via their respective binding sites.
- (3)
- The Trans co-operation model: Kindlin and talin each bind to different β subunit cytoplasmic tails and then interact with each other to form integrin clustering at focal adhesions.
5. ‘Outside–In’ Signalling
Extracellular Ligand Binding
6. Other Factors That Can (Artificially) Modulate Integrin Function
6.1. Divalent Cations
6.2. Integrin-Activating Antibodies
7. Our Findings on Integrin Activation and Axon Regeneration
8. The Outlook for Nervous System Repair
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Publication | Andrews et al., 2009 | Tan et al., 2012 | Cheah et al., 2016 |
Molecule | α9 integrin | Kindlin-1 | α9 integrin + kindlin-1 |
In vitro model | Adult rat dissociated dorsal root ganglia (DRG) neurons plated on laminin (control) or tenascin-C (TN-C). | Adult rat dissociated DRG neurons plated on laminin (control) or aggrecan. | Adult rat dissociated DRG neurons plated on laminin (control), aggrecan, TN-C, or aggrecan + TN-C. |
In vitro results | Neurite outgrowth when grown on TN-C rescued by expression of α9 integrin to levels similar to growth on laminin. Growth was significantly higher than wildtype neurons grown on TN-C. | Neurite outgrowth when grown on aggrecan rescued by expression of kindlin-1 to levels similar to growth on laminin. Growth was significantly higher than wildtype neurons grown on aggrecan. | Neurite outgrowth of DRG neurons when grown on aggrecan + TN-C rescued by combined expression of α9 integrin and kindlin-1 to levels similar to growth on laminin. Growth was significantly higher than neurons expressing α9 integrin or kindlin-1 alone grown on aggrecan + TN-C. |
In vivo model | Unilateral cervical dorsal root crush injury (C5–C8) *, examined 6 weeks post-injury. | Unilateral cervical dorsal root crush injury (C5–C8), examined 6 weeks post-injury. | Unilateral cervical dorsal root crush injury (C5–C8); examined 12 weeks post-injury **. |
Virus transduction | AAV2-α9 integrin injected into C6, C7 DRGs. AAV2-fGFP as control. | AAV2-kindlin1-mCherry injected into C6, C7 DRGs. AAV2-mCherry and AAV2-fGFP as controls. | AAV5-kindlin1-GFP and AAV-α9integrin-V5 injected into C6, C7 DRGs. AAV5-fGFP as control. |
Anatomical results | |||
α9 integrin-expressing axons grew into the TN-C-rich DREZ. Control axons did not grow into the CNS at all. | Kindlin1-expressing axons grew beyond the DREZ and into the dorsal horn. Control axons did not grow into the CNS at all. | Axons co-expressing α9 integrin and kindlin-1 grew beyond the TN-C-and-CSPG-rich DREZ and into the dorsal horn topographically, and also within the spinal cord (cuneate fasciculus) to the medulla for a distance of up to 25 mm. Control axons did not grow into the CNS at all. | |
Behavioural tests | Behavioural recovery to pre-operative levels in α9 integrin group in thermal pain sensory test. | Behavioural recovery to pre-operative levels in kindlin-1 group occurred in both the mechanical pressure and thermal pain sensory tests. | Significant behavioural recovery to near pre-operative levels in combined treatment group in mechanical pressure and thermal pain sensory tests, and ladder-walking (limb proprioception) test. |
Electro-physiology | N/A | N/A | Significant functional reconnection shown between injured dorsal roots and associated dorsal horn in combined treatment group. |
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Cheah, M.; Andrews, M.R. Integrin Activation: Implications for Axon Regeneration. Cells 2018, 7, 20. https://doi.org/10.3390/cells7030020
Cheah M, Andrews MR. Integrin Activation: Implications for Axon Regeneration. Cells. 2018; 7(3):20. https://doi.org/10.3390/cells7030020
Chicago/Turabian StyleCheah, Menghon, and Melissa R. Andrews. 2018. "Integrin Activation: Implications for Axon Regeneration" Cells 7, no. 3: 20. https://doi.org/10.3390/cells7030020
APA StyleCheah, M., & Andrews, M. R. (2018). Integrin Activation: Implications for Axon Regeneration. Cells, 7(3), 20. https://doi.org/10.3390/cells7030020