John van Geest Centre for Brain Repair

School of Clinical Medicine

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Axon Regeneration in the Central Nervous system

 

Axon Regeneration in the Central Nervous system

Many forms of brain and spinal cord (CNS)  damage cut axons. Where axons can regenerate, as in peripheral nerves, they can bring back function. However in the CNS axon regeneration fails. This is the main reason why paralysis and loss of sensation is permanent in conditions such as spinal cord injury. Many laboratories are therefore working to find out how to make it possible for cut axons in the spinal cord and brain to regenerate. Axon regeneration in spinal injury patients is one of the best hopes of returning useful function. Axon regeneration in the CNS fails for two reasons. First because the environment surrounding CNS lesions is inhibitory to axon growth, and second because most CNS axons only mount a feeble regeneration response after they are cut. The Fawcett laboratory is working on both these problems.

 

Integrin vesicles moving inside an axon growth cone

Proteoglycans and the glial scar

The lab has been involved in finding out why the glial scar that develops after CNS injuries is inhibitory to axon regeneration. The major inhibitory molecules are chondroitin sulphate proteoglycans (CSPGs). Semaphorins and ephrins are also present in the core of the scar. Proteoglycans have a protein core to which are attached highly charged sulfated glycosaminoglycan (sugar) chains. If the sugar chains are digested away with chondroitinase much of the inhibitory activity of the proteolgycans is lost, and this promotes promotes axon regeneration in the damaged brain and spinal cord.

The proteoglycans in the glial scar also inhibit conduction of action potentials in undamaged nerve fibres close to spinal cord injuries.

Zhao RR, Andrews MR, Wang D, Warren P, Gullo M, Schnell L, Schwab ME, Fawcett JW (2013) Combination treatment with anti-Nogo-A and chondroitinase ABC is more effective than single treatments at enhancing functional recovery after spinal cord injury. Eur J Neurosci 38:2946-2961.

Lin R, Rosahl TW, Whiting PJ, Fawcett JW, Kwok JC (2011) 6-sulphated chondroitins have a positive influence on axonal regeneration. PLoS ONE 6:e21499.

Chew DJ, Fawcett JW, Andrews MR (2012) The challenges of long-distance axon regeneration in the injured CNS. Prog Brain Res 201:253-294.

Zhao RR, Muir EM, Alves JN, Rickman H, Allan AY, Kwok JC, Roet KC, Verhaagen J, Schneider BL, Bensadoun JC, Ahmed SG, Yanez-Munoz RJ, Keynes RJ, Fawcett JW, Rogers JH (2011) Lentiviral vectors express chondroitinase ABC in cortical projections and promote sprouting of injured corticospinal axons. J Neurosci Methods 201:228-238.

S. Hunanyan, G. Garcia-Alias, V. Alessi, J. M. Levine, J. W. Fawcett, L. M. Mendell, and V. L. Arvanian. Role of chondroitin sulfate proteoglycans in axonal conduction in Mammalian spinal cord. J.Neurosci. 30 (23):7761-7769, 2010.

L. Arvanian, L. Schnell, L. Lou, R. Golshani, A. Hunanyan, A. Ghosh, D. D. Pearse, J. K. Robinson, M. E. Schwab, J. W. Fawcett, and L. M. Mendell. Chronic spinal hemisection in rats induces a progressive decline in transmission in uninjured fibers to motoneurons. Exp.Neurol. 216 (2):471-480, 2009.

Bradbury,E.J., Moon,L.D.F., Popat,R.J., King,V.R., Bennett,G.S., Patel,P.N., Fawcett,J.W. & McMahon,S.B. (2002) Chondroitinase ABC promotes axon regeneration and functional recovery following spinal cord injury. Nature, 416, 636-640.

 

Intrinsic regenerative ability of axons

While axons in peripheral nerve regenerate well, those in the CNS regenerate poorly. This is not only due to the inhibitory molecules of the CNS. Many CNS axons mount little or no regenerative response after they are cut, in contrast to peripheral axons which make a vigorous effort to regrow, and embryonic axons regenerate more vigorously than adult axons. We have developed a tissue culture model in which we can see this developmental change: young axons regenerate when cut, but mature axons fail.

We are working to restore regeneration to adult axons by enabling transport of growth-related molecules such as integrins into axons, and by encouraging local protein translation in axons.

Trafficking: Integrins and the cell surface in axon regeneration

Cell process interact with the surrounding extracellular matrix mostly through various receptors, particularly integrins and growth factor receptors. Axons need signals from these receptors in order to regenerate in the damaged CNS. In particular they need to have on their surface integrins that can interact with the matrix glycoproteins found there. The correct integrin is called Alpha9, which interacts with tenascin, which is present in large amounts in the damaged CNS and is the main matrix glycoprotein of the CNS. We find that alpha9 integrin expressed in sensory neurons allows them to regenerate vigorously in the spinal cord and restore sensory function as long as we also express kindlin to activate the integrins.

In addition to using integrins to stimulate axon regeneration, we have studied them as an example of an essential molecule that is needed for regeneration. By finding out what happens to integrins in axons that succeed or fail in regeneration we can discover general rules about regeneration failure. Using this strategy we have found that integrins and several types of growth factor receptors necessary for axon growth become excluded from axons as they mature. The maturation process gives axons their specific structure and function, but it also removes essential growth molecules from axons. The integrins and other receptors are transported in packages called recycling endosomes. We are working out how to get these endosomes and the receptors which they contain into mature axons so that the axons can regenerate after injury.

Franssen EH, Zhao RR, Koseki H, Kanamarlapudi V, Hoogenraad CC, Eva R, Fawcett JW (2015) Exclusion of integrins from CNS axons is regulated by Arf6 activation and the AIS, J. Neurosci.

Tan CL, Kwok JC, Heller JP, Zhao R, Eva R, Fawcett JW (2015) Full length talin stimulates integrin activation and axon regeneration. Mol Cell Neurosci.

Kappagantula S, Andrews MR, Cheah M, Abad-Rodriguez J, Dotti CG, Fawcett JW (2014) Neu3 sialidase-mediated ganglioside conversion is necessary for axon regeneration and is blocked in CNS axons. J Neurosci 34:2477-2492.

Bradke F, Fawcett JW, Spira ME (2012) Assembly of a new growth cone after axotomy: the precursor to axon regeneration. Nat Rev Neurosci 13:183-193.

Gumy LF, Chew DJ, Tortosa E, Katrukha EA, Kapitein LC, Tolkovsky AM, Hoogenraad CC, Fawcett JW (2013) The kinesin-2 family member KIF3C regulates microtubule dynamics and is required for axon growth and regeneration. J Neurosci 33:11329-11345.

Tan CL, Andrews MR, Kwok JC, Heintz TG, Gumy LF, Fassler R, Fawcett JW (2012) Kindlin-1 enhances axon growth on inhibitory chondroitin sulfate proteoglycans and promotes sensory axon regeneration. J Neurosci 32:7325-7335.

Eva R, Crisp S, Marland JR, Norman JC, Kanamarlapudi V, Ffrench-Constant C, Fawcett JW (2012) ARF6 Directs Axon Transport and Traffic of Integrins and Regulates Axon Growth in Adult DRG Neurons. J Neurosci 32:10352-10364.

Tan CL, Kwok JC, Patani R, Ffrench-Constant C, Chandran S, Fawcett JW (2011) Integrin Activation Promotes Axon Growth on Inhibitory Chondroitin Sulfate Proteoglycans by Enhancing Integrin Signaling. J Neurosci 31:6289-6295.

Eva, E. Dassie, P. T. Caswell, G. Dick, C. Ffrench-Constant, J. C. Norman, and J. W. Fawcett. 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. 30 (35):11654-11669, 2010.

R. Andrews, S. Czvitkovich, E. Dassie, C. F. Vogelaar, A. Faissner, B. Blits, F. H. Gage, C. Ffrench-Constant, and J. W. Fawcett. Alpha9 integrin promotes neurite outgrowth on tenascin-C and enhances sensory axon regeneration. J.Neurosci 29 (17):5546-5557, 2009.

 

Protein translation in axons: The lab has been collaborating with the Holt lab in the Dept Physiology Development and Neuroscience to show that successful regeneration requires that axons are able to synthesize new proteins near the site of axon damage. Axons that have a high regenerative potential have larger amounts of ribosomes and other protein synthesis machinery in the axon than axons with low regenerative potential. The mRNA species in axons are mostly related to the cytoskeleton and the control of cytoskeletal polymerisation. Projects in the laboratory are examining the functional role of axonal mRNAs. It is probable that if CNS axons contained the same mRNAs and protein synthesis machinery as PNS axons they would regenerate better. However, CNS axons do not transport ribosomes; we are working out how to change CNS axons so that they will transport these materials.

Gumy LF, Yeo GS, Tung YC, Zivraj KH, Willis D, Coppola G, Lam BY, Twiss JL, Holt CE, Fawcett JW (2011) Transcriptome analysis of embryonic and adult sensory axons reveals changes in mRNA repertoire localization. RNA 17:85-98.

L.F. Gumy, C. L. Tan, and J. W. Fawcett. The role of local protein synthesis and degradation in axon regeneration. Exp.Neurol. 223:28-37, 2009.

C.F. Vogelaar, N. M. Gervasi, L. F. Gumy, D. J. Story, R. Raha-Chowdhury, K. M. Leung, C. E. Holt, and J. W. Fawcett. Axonal mRNAs: characterisation and role in the growth and regeneration of dorsal root ganglion axons and growth cones. Mol.Cell Neurosci 42 (2):102-115, 2009.

Vogelaar,C.M. & Fawcett,J.W. (2008) Axonal mRNA in regeneration. In Muller,H.W. (ed), Neural Degeneration and Repair. Wiley.

Verma,P., Chierzi,S., Codd,A.M., Campbell,D.S., Meyer,R.L., Holt,C.E. & Fawcett,J.W. (2005) Axonal Protein Synthesis and Degradation are Necessary for Efficient Growth Cone Regeneration. J.Neurosci., 25, 331-342.

Verma,P. & Fawcett,J.W. (2004) Spinal Cord Injury: Making the Reconnection. In Baehr,M. (ed), Neuroprotection- Models, Mechanisms, Therapies. Wiley, Weinheim.

 

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