Abstract
Axons in the CNS do not regrow after injury, whereas lesioned axons in the peripheral nervous system (PNS) regenerate. Lesioned CNS axons form characteristic swellings at their tips known as retraction bulbs, which are the nongrowing counterparts of growth cones. Although much progress has been made in identifying intracellular and molecular mechanisms that regulate growth cone locomotion and axonal elongation, a comprehensive understanding of how retraction bulbs form and why they are unable to grow is still elusive. Here we report the analysis of the morphological and intracellular responses of injured axons in the CNS compared with those in the PNS. We show that retraction bulbs of injured CNS axons increase in size over time, whereas growth cones of injured PNS axons remain constant. Retraction bulbs contain a disorganized microtubule network, whereas growth cones possess the typical bundling of microtubules. Usingin vivoimaging, we find that pharmacological disruption of microtubules in growth cones transforms them into retraction bulb-like structures whose growth is inhibited. Correspondingly, microtubule destabilization of sensory neurons in cell culture induces retraction bulb formation. Conversely, microtubule stabilization prevents the formation of retraction bulbs and decreases axonal degenerationin vivo. Finally, microtubule stabilization enhances the growth capacity of CNS neurons cultured on myelin. Thus, the stability and organization of microtubules define the fate of lesioned axonal stumps to become either advancing growth cones or nongrowing retraction bulbs. Our data pinpoint microtubules as a key regulatory target for axonal regeneration.
References
59
Referenced
362
10.1002/jnr.20170
10.1002/ana.410020612
10.1111/j.1471-4159.2005.03635.x
10.1016/S0896-6273(00)80410-9
10.1523/JNEUROSCI.22-21-09358.2002
/ J Neurosci / Growth cone turning induced by direct local modification of microtubule dynamics by Buck (2002)10.1016/0896-6273(92)90025-9
10.1016/S0896-6273(02)00826-7
10.1038/nrn1788
10.1038/375592a0
10.1016/0092-8674(95)90182-5
10.1016/S0896-6273(03)00633-0
10.1523/JNEUROSCI.19-20-08894.1999
/ J Neurosci / Reorganization and movement of microtubules in axonal growth cones and developing interstitial branches by Dent (1999)10.1021/bi00007a014
10.1016/j.ceb.2004.12.011
10.1016/0092-8674(95)90425-5
10.1083/jcb.200301080
10.1111/j.1600-0854.2004.00196.x
10.1083/jcb.121.4.867
10.1016/S0896-6273(00)00084-2
10.1083/jcb.107.4.1505
10.1523/JNEUROSCI.23-04-01416.2003
/ J Neurosci / Rho kinase inhibition enhances axonal regeneration in the injured CNS by Fournier (2003)10.1523/JNEUROSCI.15-10-06445.1995
/ J Neurosci / Axotomy-induced axonal degeneration is mediated by calcium influx through ion-specific channels by George (1995)10.1016/S0092-8674(00)80689-3
10.1083/jcb.100.2.384
10.1006/exnr.2001.7734
10.1038/nrn1624
10.1146/annurev.neuro.26.010302.081139
10.1083/jcb.152.5.1033
10.1038/nm1229
10.1523/JNEUROSCI.18-09-03241.1998
/ J Neurosci / Massive mitochondrial degeneration in motor neurons triggers the onset of amyotrophic lateral sclerosis in mice expressing a mutant SOD1 by Kong (1998)10.1111/j.1365-2818.1969.tb00664.x
/ J Microsc / An electron-microscopic study of cholinesterase distribution in the rat adrenal medulla by Lewis (1969)10.1006/exnr.1995.1041
10.1523/JNEUROSCI.09-04-01452.1989
/ J Neurosci / Rapid induction of the major embryonic α-tubulin mRNA, Tα1, during nerve regeneration in adult rats by Miller (1989)10.1074/jbc.M510934200
10.1038/nrn1905
/ Nat Rev Neurosci / In vivo imaging of the diseased nervous system by Misgeld (2006)10.1074/jbc.272.38.23851
10.1242/jcs.104.3.917
/ J Cell Sci / The regulation of bidirectional mitochondrial transport is coordinated with axonal outgrowth by Morris (1993)10.1523/JNEUROSCI.15-02-01545.1995
/ J Neurosci / Sensory neurons selectively upregulate synthesis and transport of the βIII-tubulin protein during axonal regeneration by Moskowitz (1995)10.1016/S0896-6273(02)00702-X
10.1523/JNEUROSCI.19-20-08979.1999
/ J Neurosci / Bovine CNS myelin contains neurite growth-inhibitory activity associated with chondroitin sulfate proteoglycans by Niederost (1999)10.1002/(SICI)1097-0169(1997)36:2<125::AID-CM3>3.0.CO;2-8
10.1523/JNEUROSCI.23-36-11479.2003
/ J Neurosci / Effects of neurotoxic and neuroprotective agents on peripheral nerve regeneration assayed by time-lapse imaging in vivo by Pan (2003)- Ramon y Cajal S (1928) Degeneration and regeneration of the nervous system (Oxford UP, London).
10.1016/0896-6273(90)90440-Q
10.1083/jcb.115.2.381
10.1083/jcb.200203038
10.1038/nn1295
10.1016/j.mcn.2004.06.004
10.1038/nrn1326
10.1038/nn1193
10.1523/JNEUROSCI.17-02-00646.1997
/ J Neurosci / A transcription-dependent switch controls competence of adult neurons for distinct modes of axon growth by Smith (1997)10.1523/JNEUROSCI.2111-05.2005
10.1083/jcb.141.1.227
10.1083/jcb.115.2.345
10.1523/JNEUROSCI.0994-04.2004
10.1016/S0960-9822(02)70682-9
10.1038/nrm1260
10.1073/pnas.66.4.1206
-
Ylera B Bradke F (2006) Model organisms in spinal cord regeneration, Stimulating growth potential in mammalian neurons (Wiley-VCH, Edinburgh).
(
10.1002/9783527610365.ch3
)
Dates
Type | When |
---|---|
Created | 18 years ago (Aug. 22, 2007, 12:23 p.m.) |
Deposited | 1 year, 6 months ago (Feb. 17, 2024, 9:19 a.m.) |
Indexed | 3 days, 1 hour ago (Aug. 29, 2025, 5:58 a.m.) |
Issued | 18 years ago (Aug. 22, 2007) |
Published | 18 years ago (Aug. 22, 2007) |
Published Online | 18 years ago (Aug. 22, 2007) |
Published Print | 18 years ago (Aug. 22, 2007) |
@article{Ert_rk_2007, title={Disorganized Microtubules Underlie the Formation of Retraction Bulbs and the Failure of Axonal Regeneration}, volume={27}, ISSN={1529-2401}, url={http://dx.doi.org/10.1523/jneurosci.0612-07.2007}, DOI={10.1523/jneurosci.0612-07.2007}, number={34}, journal={The Journal of Neuroscience}, publisher={Society for Neuroscience}, author={Ertürk, Ali and Hellal, Farida and Enes, Joana and Bradke, Frank}, year={2007}, month=aug, pages={9169–9180} }