EFA6 in Axon Regeneration, As a Microtubule Regulator and As a Guanine Nucleotide Exchange Factor

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2021 Jun 2

PMID 34073530

Citations 2

Authors

Gilberto Gonzalez

Lizhen Chen

Affiliations

Soon will be listed here.

Abstract

Axon regeneration after injury is a conserved biological process that involves a large number of molecular pathways, including rapid calcium influx at injury sites, retrograde injury signaling, epigenetic transition, transcriptional reprogramming, polarized transport, and cytoskeleton reorganization. Despite the numerous efforts devoted to understanding the underlying cellular and molecular mechanisms of axon regeneration, the search continues for effective target molecules for improving axon regeneration. Although there have been significant historical efforts towards characterizing pro-regenerative factors involved in axon regeneration, the pursuit of intrinsic inhibitors is relatively recent. EFA6 (exchange factor for ARF6) has been demonstrated to inhibit axon regeneration in different organisms. EFA6 inhibition could be a promising therapeutic strategy to promote axon regeneration and functional recovery after axon injury. This review summarizes the inhibitory role on axon regeneration through regulating microtubule dynamics and through affecting ARF6 (ADP-ribosylation factor 6) GTPase-mediated integrin transport.

Citing Articles

Arf6 as a therapeutic target: Structure, mechanism, and inhibitors.

Sun D, Guo Y, Tang P, Li H, Chen L Acta Pharm Sin B. 2023; 13(10):4089-4104.

PMID: 37799386 PMC: 10547916. DOI: 10.1016/j.apsb.2023.06.008.

Retraction: Gonzalez, G.; Chen, L. EFA6 in Axon Regeneration, as a Microtubule Regulator and as a Guanine Nucleotide Exchange Factor. 2021, , 1325.

Gonzalez G, Chen L Cells. 2022; 11(11).

PMID: 35681551 PMC: 9179864. DOI: 10.3390/cells11111721.

References

Qu Y, Hahn I, Lees M, Parkin J, Voelzmann A, Dorey K . Efa6 protects axons and regulates their growth and branching by inhibiting microtubule polymerisation at the cortex. Elife. 2019; 8. PMC: 6884004. DOI: 10.7554/eLife.50319. View

Song Y, Ori-McKenney K, Zheng Y, Han C, Jan L, Jan Y . Regeneration of Drosophila sensory neuron axons and dendrites is regulated by the Akt pathway involving Pten and microRNA bantam. Genes Dev. 2012; 26(14):1612-25. PMC: 3404388. DOI: 10.1101/gad.193243.112. View

Nwagbara B, Faris A, Bearce E, Erdogan B, Ebbert P, Evans M . TACC3 is a microtubule plus end-tracking protein that promotes axon elongation and also regulates microtubule plus end dynamics in multiple embryonic cell types. Mol Biol Cell. 2014; 25(21):3350-62. PMC: 4214782. DOI: 10.1091/mbc.E14-06-1121. View

ORourke S, Christensen S, Bowerman B . Caenorhabditis elegans EFA-6 limits microtubule growth at the cell cortex. Nat Cell Biol. 2010; 12(12):1235-41. PMC: 3236679. DOI: 10.1038/ncb2128. View

Kim K, Tang N, Piggott C, Andrusiak M, Park S, Zhu M . Expanded genetic screening in identifies new regulators and an inhibitory role for NAD in axon regeneration. Elife. 2018; 7. PMC: 6281318. DOI: 10.7554/eLife.39756. View

Donaldson J, Jackson C . ARF family G proteins and their regulators: roles in membrane transport, development and disease. Nat Rev Mol Cell Biol. 2011; 12(6):362-75. PMC: 3245550. DOI: 10.1038/nrm3117. View

Miyazaki H, Yamazaki M, Watanabe H, Maehama T, Yokozeki T, Kanaho Y . The small GTPase ADP-ribosylation factor 6 negatively regulates dendritic spine formation. FEBS Lett. 2005; 579(30):6834-8. DOI: 10.1016/j.febslet.2005.11.022. View

Erez H, Malkinson G, Prager-Khoutorsky M, De Zeeuw C, Hoogenraad C, Spira M . Formation of microtubule-based traps controls the sorting and concentration of vesicles to restricted sites of regenerating neurons after axotomy. J Cell Biol. 2007; 176(4):497-507. PMC: 2063984. DOI: 10.1083/jcb.200607098. View

Franco M, Peters P, Boretto J, van Donselaar E, Neri A, DSouza-Schorey C . EFA6, a sec7 domain-containing exchange factor for ARF6, coordinates membrane recycling and actin cytoskeleton organization. EMBO J. 1999; 18(6):1480-91. PMC: 1171237. DOI: 10.1093/emboj/18.6.1480. View

10.

Rosenzweig E, Courtine G, Jindrich D, Brock J, Ferguson A, Strand S . Extensive spontaneous plasticity of corticospinal projections after primate spinal cord injury. Nat Neurosci. 2010; 13(12):1505-10. PMC: 3144760. DOI: 10.1038/nn.2691. View

11.

Weisenberg R . Microtubule formation in vitro in solutions containing low calcium concentrations. Science. 1972; 177(4054):1104-5. DOI: 10.1126/science.177.4054.1104. View

12.

Kaas J, Qi H, Burish M, Gharbawie O, Onifer S, Massey J . Cortical and subcortical plasticity in the brains of humans, primates, and rats after damage to sensory afferents in the dorsal columns of the spinal cord. Exp Neurol. 2007; 209(2):407-16. PMC: 2268113. DOI: 10.1016/j.expneurol.2007.06.014. View

13.

Flynn K, Hellal F, Neukirchen D, Jacob S, Tahirovic S, Dupraz S . ADF/cofilin-mediated actin retrograde flow directs neurite formation in the developing brain. Neuron. 2012; 76(6):1091-107. DOI: 10.1016/j.neuron.2012.09.038. View

14.

Nishida E, Sakai H . Calcium-sensitivity of the microtubule reassembly system. Difference between crude brain extract and purified microtubular proteins. J Biochem. 1977; 82(1):303-6. DOI: 10.1093/oxfordjournals.jbchem.a131685. View

15.

Samara C, Rohde C, Gilleland C, Norton S, Haggarty S, Yanik M . Large-scale in vivo femtosecond laser neurosurgery screen reveals small-molecule enhancer of regeneration. Proc Natl Acad Sci U S A. 2010; 107(43):18342-7. PMC: 2972960. DOI: 10.1073/pnas.1005372107. View

16.

Pecreaux J, Roper J, Kruse K, Julicher F, Hyman A, Grill S . Spindle oscillations during asymmetric cell division require a threshold number of active cortical force generators. Curr Biol. 2006; 16(21):2111-22. DOI: 10.1016/j.cub.2006.09.030. View

17.

Yanik M, Cinar H, Cinar H, Chisholm A, Jin Y, Ben-Yakar A . Neurosurgery: functional regeneration after laser axotomy. Nature. 2004; 432(7019):822. DOI: 10.1038/432822a. View

18.

Eva R, Dassie E, Caswell P, Dick G, ffrench-Constant C, Norman J . Rab11 and its effector Rab coupling protein contribute to the trafficking of beta 1 integrins during axon growth in adult dorsal root ganglion neurons and PC12 cells. J Neurosci. 2010; 30(35):11654-69. PMC: 6633432. DOI: 10.1523/JNEUROSCI.2425-10.2010. View

19.

Stone M, Nguyen M, Tao J, Allender D, Rolls M . Global up-regulation of microtubule dynamics and polarity reversal during regeneration of an axon from a dendrite. Mol Biol Cell. 2010; 21(5):767-77. PMC: 2828963. DOI: 10.1091/mbc.e09-11-0967. View

20.

Lasiecka Z, Winckler B . Mechanisms of polarized membrane trafficking in neurons -- focusing in on endosomes. Mol Cell Neurosci. 2011; 48(4):278-87. PMC: 3205304. DOI: 10.1016/j.mcn.2011.06.013. View