[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 54.163.147.69. Please contact the publisher to request reinstatement.
[Skip to Content Landing]
Figure.
Axon regeneration in the rat optic nerve. Longitudinal sections were stained with antibodies to the protein GAP-43 two weeks after optic nerve injury to visualize regenerating axons. Asterisks denote the injury site. Scalebar indicates 250 μm. A, Almost no regeneration occurs in the absence of further stimulation. B, Lens injury (LI) or zymosan induces intraocular inflammation and enables retinal ganglion cells (RGCs) to regenerate axons through the optic nerve. C, Oncomodulin (Ocm) plus a cyclic adenosine monophosphate (cAMP) analogue, when delivered from slow-release polymeric beads, mimic LI effects. D, An Ocm receptor antagonist, P1, suppresses LI effects. E, Expression of the bacterial enzyme C3 ribosyltransferase (C3) in RGCs blocks the activity of Ras homologue member A and enables axons to ignore inhibitory signals in their environment. The expression of C3 produces only modest levels of regeneration but greatly enhances the amount of regeneration resulting from intraocular inflammation.

Axon regeneration in the rat optic nerve. Longitudinal sections were stained with antibodies to the protein GAP-43 two weeks after optic nerve injury to visualize regenerating axons. Asterisks denote the injury site. Scalebar indicates 250 μm. A, Almost no regeneration occurs in the absence of further stimulation. B, Lens injury (LI) or zymosan induces intraocular inflammation and enables retinal ganglion cells (RGCs) to regenerate axons through the optic nerve.9,10 C, Oncomodulin (Ocm) plus a cyclic adenosine monophosphate (cAMP) analogue, when delivered from slow-release polymeric beads, mimic LI effects.11 D, An Ocm receptor antagonist, P1, suppresses LI effects.12 E, Expression of the bacterial enzyme C3 ribosyltransferase (C3) in RGCs blocks the activity of Ras homologue member A and enables axons to ignore inhibitory signals in their environment. The expression of C3 produces only modest levels of regeneration but greatly enhances the amount of regeneration resulting from intraocular inflammation.13

1.
Ramon y Cajal  S  Degeneration and Regeneration of the Nervous System.  Vol 5. New York, NY Oxford University Press1991;
2.
Aguayo  AJRasminsky  MBray  GM  et al.  Degenerative and regenerative responses of injured neurons in the central nervous system of adult mammals. Philos Trans R Soc Lond B Biol Sci 1991;331 (1261) 337- 343
PubMed
3.
Carbonetto  SEvans  DCochard  P Nerve fiber growth in culture on tissue substrata from central and peripheral nervous systems. J Neurosci 1987;7 (2) 610- 620
PubMed
4.
Savio  TSchwab  ME Rat CNS white matter, but not gray matter, is nonpermissive for neuronal cell adhesion and fiber outgrowth. J Neurosci 1989;9 (4) 1126- 1133
PubMed
5.
Schwab  METhoenen  H Dissociated neurons regenerate into sciatic but not optic nerve explants in culture irrespective of neurotrophic factors. J Neurosci 1985;5 (9) 2415- 2423
PubMed
6.
Berry  MCarlile  JHunter  A Peripheral nerve explants grafted into the vitreous body of the eye promote the regeneration of retinal ganglion cell axons severed in the optic nerve. J Neurocytol 1996;25 (2) 147- 170
PubMed
7.
Lazarov-Spiegler  OSolomon  ASZeev-Brann  ABHirschberg  DLLavie  VSchwartz  M Transplantation of activated macrophages overcomes central nervous system regrowth failure. FASEB J 1996;10 (11) 1296- 1302
PubMed
8.
Lazarov-Spiegler  OSolomon  ASSchwartz  M Peripheral nerve-stimulated macrophages simulate a peripheral nerve-like regenerative response in rat transected optic nerve. Glia 1998;24 (3) 329- 337
PubMed
9.
Leon  SYin  YNguyen  JIrwin  NBenowitz  LI Lens injury stimulates axon regeneration in the mature rat optic nerve. J Neurosci 2000;20 (12) 4615- 4626
PubMed
10.
Yin  YCui  QLi  Y  et al.  Macrophage-derived factors stimulate optic nerve regeneration. J Neurosci 2003;23 (6) 2284- 2293
PubMed
11.
Yin  YHenzl  MTLorber  B  et al.  Oncomodulin is a macrophage-derived signal for axon regeneration in retinal ganglion cells. Nat Neurosci 2006;9 (6) 843- 852
PubMed
12.
Yin  YCui  QGilbert  H  et al.  Oncomodulin links inflammation to optic nerve regeneration. Proc Natl Acad Sci U S A 2009;106 (46) 19587- 19592
PubMed
13.
Fischer  DPetkova  VThanos  SBenowitz  LI Switching mature retinal ganglion cells to a robust growth state in vivo: gene expression and synergy with RhoA inactivation. J Neurosci 2004;24 (40) 8726- 8740
PubMed
14.
Fischer  DHeiduschka  PThanos  S Lens-injury-stimulated axonal regeneration throughout the optic pathway of adult rats. Exp Neurol 2001;172 (2) 257- 272
PubMed
15.
Jo  SWang  EBenowitz  LI Ciliary neurotrophic factor is an axogenesis factor for retinal ganglion cells. Neuroscience 1999;89 (2) 579- 591
PubMed
16.
Lorber  BBerry  MLogan  A Different factors promote axonal regeneration of adult rat retinal ganglion cells after lens injury and intravitreal peripheral nerve grafting. J Neurosci Res 2008;86 (4) 894- 903
PubMed
17.
Li  YIrwin  NYin  YLanser  MBenowitz  LI Axon regeneration in goldfish and rat retinal ganglion cells: differential responsiveness to carbohydrates and cAMP. J Neurosci 2003;23 (21) 7830- 7838
PubMed
18.
Hauk  TGMüller  ALee  JSchwendener  RFischer  D Neuroprotective and axon growth promoting effects of intraocular inflammation do not depend on oncomodulin or the presence of large numbers of activated macrophages. Exp Neurol 2008;209 (2) 469- 482
PubMed
19.
Müller  AHauk  TGFischer  D Astrocyte-derived CNTF switches mature RGCs to a regenerative state following inflammatory stimulation. Brain 2007;130 (pt 12) 3308- 3320
PubMed
20.
Cui  QBenowitz  LYin  Y Does CNTF mediate the effect of intraocular inflammation on optic nerve regeneration? Brain 2008;131 (pt 6) e96- e97
PubMed10.1093/brain/awn027
21.
Fischer  DPavlidis  MThanos  S Cataractogenic lens injury prevents traumatic ganglion cell death and promotes axonal regeneration both in vivo and in culture. Invest Ophthalmol Vis Sci 2000;41 (12) 3943- 3954
PubMed
22.
Irwin  NLi  Y-MO’Toole  JEBenowitz  LI Mst3b, a purine-sensitive Ste20-like protein kinase, regulates axon outgrowth. Proc Natl Acad Sci U S A 2006;103 (48) 18320- 18325
PubMed
23.
Lorber  BHowe  MLBenowitz  LIIrwin  N Mst3b, an Ste20-like kinase, regulates axon regeneration in the mature CNS and PNS. Nat Neurosci 2009;12 (11) 1407- 1414
PubMed
24.
Park  KKLiu  KHu  Y  et al.  Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science 2008;322 (5903) 963- 966
PubMed
25.
Smith  PDSun  FPark  KK  et al.  SOCS3 deletion promotes optic nerve regeneration in vivo. Neuron 2009;64 (5) 617- 623
PubMed
26.
Goldberg  JLKlassen  MPHua  YBarres  BA Amacrine-signaled loss of intrinsic axon growth ability by retinal ganglion cells. Science 2002;296 (5574) 1860- 1864
PubMed
27.
Moore  DLBlackmore  MGHu  Y  et al.  KLF family members regulate intrinsic axon regeneration ability. Science 2009;326 (5950) 298- 301
PubMed
28.
Ming  G-LSong  H-JBerninger  BHolt  CETessier-Lavigne  MPoo  M-M cAMP-dependent growth cone guidance by netrin-1. Neuron 1997;19 (6) 1225- 1235
PubMed
29.
Song  HMing  GHe  Z  et al.  Conversion of neuronal growth cone responses from repulsion to attraction by cyclic nucleotides. Science 1998;281 (5382) 1515- 1518
PubMed
30.
Meyer-Franke  AWilkinson  GAKruttgen  A  et al.  Depolarization and cAMP elevation rapidly recruit TrkB to the plasma membrane of CNS neurons. Neuron 1998;21 (4) 681- 693
PubMed
31.
Cai  DDeng  KMellado  WLee  JRatan  RFilbin  M Arginase I and polyamines act downstream from cyclic AMP in overcoming inhibition of axonal growth MAG and myelin in vitro. Neuron 2002;35 (4) 711- 719
PubMed
32.
Park  KKHu  YMuhling  J  et al.  Cytokine-induced SOCS expression is inhibited by cAMP analogue: impact on regeneration in injured retina. Mol Cell Neurosci 2009;41 (3) 313- 324
PubMed
33.
Deng  KHe  HQiu  JLorber  BBryson  JBFilbin  MT Increased synthesis of spermidine as a result of upregulation of arginase I promotes axonal regeneration in culture and in vivo. J Neurosci 2009;29 (30) 9545- 9552
PubMed
34.
Monsul  NTGeisendorfer  ARHan  PJ  et al.  Intraocular injection of dibutyryl cyclic AMP promotes axon regeneration in rat optic nerve. Exp Neurol 2004;186 (2) 124- 133
PubMed
35.
Cui  QYip  HKZhao  RCHSo  K-FHarvey  AR Intraocular elevation of cyclic AMP potentiates ciliary neurotrophic factor-induced regeneration of adult rat retinal ganglion cell axons. Mol Cell Neurosci 2003;22 (1) 49- 61
PubMed
36.
Müller  AHauk  TGLeibinger  MMarienfeld  RFischer  D Exogenous CNTF stimulates axon regeneration of retinal ganglion cells partially via endogenous CNTF. Mol Cell Neurosci 2009;41 (2) 233- 246
PubMed
37.
Yin  YKurimoto  TCen  LGilbert  HYang  YBenowitz  LI  Oncomodulin and cAMP interact in multiple ways to promote optic nerve regeneration.  Program and abstracts of the Society for Neuroscience Annual Meeting October 17-21, 2009 Chicago, IllinoisProgram 32.11
38.
Villegas-Pérez  MPVidal-Sanz  MBray  GMAguayo  AJ Influences of peripheral nerve grafts on the survival and regrowth of axotomized retinal ganglion cells in adult rats. J Neurosci 1988;8 (1) 265- 280
PubMed
39.
Chierzi  SCenni  MCMaffei  L  et al.  Protection of retinal ganglion cells and preservation of function after optic nerve lesion in bcl-2 transgenic mice. Vision Res 1998;38 (10) 1537- 1543
PubMed
40.
Malik  JMIShevtsova  ZBähr  MKügler  S Long-term in vivo inhibition of CNS neurodegeneration by Bcl-XL gene transfer. Mol Ther 2005;11 (3) 373- 381
PubMed
41.
Goldberg  JLEspinosa  JSXu  YDavidson  NKovacs  GTABarres  BA Retinal ganglion cells do not extend axons by default: promotion by neurotrophic signaling and electrical activity. Neuron 2002;33 (5) 689- 702
PubMed
42.
Mey  JThanos  S Intravitreal injections of neurotrophic factors support the survival of axotomized retinal ganglion cells in adult rats in vivo. Brain Res 1993;602 (2) 304- 317
PubMed
43.
Weise  JIsenmann  SKlöcker  N  et al.  Adenovirus-mediated expression of ciliary neurotrophic factor (CNTF) rescues axotomized rat retinal ganglion cells but does not support axonal regeneration in vivo. Neurobiol Dis 2000;7 (3) 212- 223
PubMed
44.
Mansour-Robaey  SClarke  DBWang  Y-CBray  GMAguayo  AJ Effects of ocular injury and administration of brain-derived neurotrophic factor on survival and regrowth of axotomized retinal ganglion cells. Proc Natl Acad Sci U S A 1994;91 (5) 1632- 1636
PubMed
45.
Di Polo  AAigner  LJDunn  RJBray  GMAguayo  AJ Prolonged delivery of brain-derived neurotrophic factor by adenovirus-infected Müller cells temporarily rescues injured retinal ganglion cells. Proc Natl Acad Sci U S A 1998;95 (7) 3978- 3983
PubMed
46.
Cohen  ABray  GMAguayo  AJ Neurotrophin-4/5 (NT-4/5) increases adult rat retinal ganglion cell survival and neurite outgrowth in vitro. J Neurobiol 1994;25 (8) 953- 959
PubMed
47.
Peinado-Ramón  PSalvador  MVillegas-Peréz  MPVidal-Sanz  M Effects of axotomy and intraocular administration of NT-4, NT-3, and brain-derived neurotrophic factor on the survival of adult rat retinal ganglion cells: a quantitative in vivo study. Invest Ophthalmol Vis Sci 1996;37 (4) 489- 500
PubMed
48.
Carmignoto  GMaffei  LCandeo  PCanella  RComelli  C Effect of NGF on the survival of rat retinal ganglion cells following optic nerve section. J Neurosci 1989;9 (4) 1263- 1272
PubMed
49.
Kermer  PKlöcker  NLabes  MBähr  M Insulin-like growth factor-I protects axotomized rat retinal ganglion cells from secondary death via PI3-K-dependent Akt phosphorylation and inhibition of caspase-3 In vivo. J Neurosci 2000;20 (2) 2- 8
PubMed
50.
Frank  TSchlachetzki  JCMGöricke  B  et al.  Both systemic and local application of granulocyte-colony stimulating factor (G-CSF) is neuroprotective after retinal ganglion cell axotomy. BMC Neurosci 2009;1049- 58
PubMed
51.
Koeberle  PDBall  AK Effects of GDNF on retinal ganglion cell survival following axotomy. Vision Res 1998;38 (10) 1505- 1515
PubMed
52.
Yan  QWang  JMatheson  CRUrich  JL Glial cell line-derived neurotrophic factor (GDNF) promotes the survival of axotomized retinal ganglion cells in adult rats: comparison to and combination with brain-derived neurotrophic factor (BDNF). J Neurobiol 1999;38 (3) 382- 390
PubMed
53.
Koeberle  PDBall  AK Neurturin enhances the survival of axotomized retinal ganglion cells in vivo: combined effects with glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor. Neuroscience 2002;110 (3) 555- 567
PubMed
54.
Pernet  VDi Polo  A Synergistic action of brain-derived neurotrophic factor and lens injury promotes retinal ganglion cell survival, but leads to optic nerve dystrophy in vivo. Brain 2006;129 (pt 4) 1014- 1026
PubMed
55.
Kermer  PKlöcker  NLabes  MBähr  M Inhibition of CPP32-like proteases rescues axotomized retinal ganglion cells from secondary cell death in vivo. J Neurosci 1998;18 (12) 4656- 4662
PubMed
56.
Kermer  PKlöcker  NBähr  M Long-term effect of inhibition of ced 3-like caspases on the survival of axotomized retinal ganglion cells in vivo. Exp Neurol 1999;158 (1) 202- 205
PubMed
57.
Kermer  PAnkerhold  RKlöcker  NKrajewski  SReed  JCBähr  M Caspase-9: involvement in secondary death of axotomized rat retinal ganglion cells in vivo. Brain Res Mol Brain Res 2000;85 (1-2) 144- 150
PubMed
58.
Weishaupt  JHDiem  RKermer  PKrajewski  SReed  JCBähr  M Contribution of caspase-8 to apoptosis of axotomized rat retinal ganglion cells in vivo. Neurobiol Dis 2003;13 (2) 124- 135
PubMed
59.
Weise  JIsenmann  SBähr  M Increased expression and activation of poly(ADP-ribose) polymerase (PARP) contribute to retinal ganglion cell death following rat optic nerve transection. Cell Death Differ 2001;8 (8) 801- 807
PubMed
60.
Koeberle  PDBall  AK Nitric oxide synthase inhibition delays axonal degeneration and promotes the survival of axotomized retinal ganglion cells. Exp Neurol 1999;158 (2) 366- 381
PubMed
61.
Swanson  KISchlieve  CRLieven  CJLevin  LA Neuroprotective effect of sulfhydryl reduction in a rat optic nerve crush model. Invest Ophthalmol Vis Sci 2005;46 (10) 3737- 3741
PubMed
62.
Sanders  EJParker  EHarvey  S Retinal ganglion cell survival in development: mechanisms of retinal growth hormone action. Exp Eye Res 2006;83 (5) 1205- 1214
PubMed
63.
Cheung  ZHLeung  MCPYip  HKWu  WSiu  FKWSo  K-F A neuroprotective herbal mixture inhibits caspase-3-independent apoptosis in retinal ganglion cells. Cell Mol Neurobiol 2008;28 (1) 137- 155
PubMed
64.
Fitzgerald  MPayne  SCBartlett  CAEvill  LHarvey  ARDunlop  SA Secondary retinal ganglion cell death and the neuroprotective effects of the calcium channel blocker lomerizine. Invest Ophthalmol Vis Sci 2009;50 (11) 5456- 5462
PubMed
65.
Sapieha  PSPeltier  MRendahl  KGManning  WCDi Polo  A Fibroblast growth factor-2 gene delivery stimulates axon growth by adult retinal ganglion cells after acute optic nerve injury. Mol Cell Neurosci 2003;24 (3) 656- 672
PubMed
66.
Cui  QLu  QSo  KFYip  HK CNTF, not other trophic factors, promotes axonal regeneration of axotomized retinal ganglion cells in adult hamsters. Invest Ophthalmol Vis Sci 1999;40 (3) 760- 766
PubMed
67.
Logan  AAhmed  ZBaird  AGonzalez  AMBerry  M Neurotrophic factor synergy is required for neuronal survival and disinhibited axon regeneration after CNS injury. Brain 2006;129 (pt 2) 490- 502
PubMed
68.
Leibinger  MMüller  AAndreadaki  AHauk  TGKirsch  MFischer  D Neuroprotective and axon growth-promoting effects following inflammatory stimulation on mature retinal ganglion cells in mice depend on ciliary neurotrophic factor and leukemia inhibitory factor. J Neurosci 2009;29 (45) 14334- 14341
PubMed
69.
Lingor  PTönges  LPieper  N  et al.  ROCK inhibition and CNTF interact on intrinsic signalling pathways and differentially regulate survival and regeneration in retinal ganglion cells. Brain 2008;131 (pt 1) 250- 263
PubMed
70.
Lorber  BBerry  MLogan  ATonge  D Effect of lens lesion on neurite outgrowth of retinal ganglion cells in vitro. Mol Cell Neurosci 2002;21 (2) 301- 311
PubMed
71.
Cui  QHarvey  AR CNTF promotes the regrowth of retinal ganglion cell axons into murine peripheral nerve grafts. Neuroreport 2000;11 (18) 3999- 4002
PubMed
72.
Cen  L-PLuo  J-MZhang  C-W  et al.  Chemotactic effect of ciliary neurotrophic factor on macrophages in retinal ganglion cell survival and axonal regeneration. Invest Ophthalmol Vis Sci 2007;48 (9) 4257- 4266
PubMed
73.
Filbin  MT Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS. Nat Rev Neurosci 2003;4 (9) 703- 713
PubMed
74.
Cafferty  WBJ McGee  AWStrittmatter  SM Axonal growth therapeutics: regeneration or sprouting or plasticity? Trends Neurosci 2008;31 (5) 215- 220
PubMed
75.
Rossignol  SSchwab  MSchwartz  MFehlings  MG Spinal cord injury: time to move? J Neurosci 2007;27 (44) 11782- 11792
PubMed
76.
Silver  JMiller  JH Regeneration beyond the glial scar. Nat Rev Neurosci 2004;5 (2) 146- 156
PubMed
77.
Goldberg  JLVargas  MEWang  JT  et al.  An oligodendrocyte lineage-specific semaphorin, Sema5A, inhibits axon growth by retinal ganglion cells. J Neurosci 2004;24 (21) 4989- 4999
PubMed
78.
Chierzi  SStrettoi  ECenni  MCMaffei  L Optic nerve crush: axonal responses in wild-type and bcl-2 transgenic mice. J Neurosci 1999;19 (19) 8367- 8376
PubMed
79.
Fischer  DHe  ZBenowitz  LI Counteracting the Nogo receptor enhances optic nerve regeneration if retinal ganglion cells are in an active growth state. J Neurosci 2004;24 (7) 1646- 1651
PubMed
80.
Lehmann  MFournier  ASelles-Navarro  I  et al.  Inactivation of Rho signaling pathway promotes CNS axon regeneration. J Neurosci 1999;19 (17) 7537- 7547
PubMed
81.
Bertrand  JWinton  MJRodriguez-Hernandez  NCampenot  RB McKerracher  L Application of Rho antagonist to neuronal cell bodies promotes neurite growth in compartmented cultures and regeneration of retinal ganglion cell axons in the optic nerve of adult rats. J Neurosci 2005;25 (5) 1113- 1121
PubMed
82.
Battisti  WPShinar  YSchwartz  MLevitt  PMurray  M Temporal and spatial patterns of expression of laminin, chondroitin sulphate proteoglycan and HNK-1 immunoreactivity during regeneration in the goldfish optic nerve. J Neurocytol 1992;21 (8) 557- 573
PubMed
83.
Ahmed  ZDent  RGLeadbeater  WESmith  CBerry  MLogan  A Matrix metalloproteases: degradation of the inhibitory environment of the transected optic nerve and the scar by regenerating axons. Mol Cell Neurosci 2005;28 (1) 64- 78
PubMed
84.
Haupt  CHuber  AB How axons see their way: axonal guidance in the visual system. Front Biosci 2008;133136- 3149
PubMed
85.
Erskine  LHerrera  E The retinal ganglion cell axon's journey: insights into molecular mechanisms of axon guidance. Dev Biol 2007;308 (1) 1- 14
PubMed
86.
McLaughlin  TO’Leary  DD Molecular gradients and development of retinotopic maps. Annu Rev Neurosci 2005;28327- 355
PubMed
87.
Wizenmann  AThies  EKlostermann  SBonhoeffer  FBähr  M Appearance of target-specific guidance information for regenerating axons after CNS lesions. Neuron 1993;11 (5) 975- 983
PubMed
88.
Bähr  MWizenmann  A Retinal ganglion cell axons recognize specific guidance cues present in the deafferented adult rat superior colliculus. J Neurosci 1996;16 (16) 5106- 5116
PubMed
89.
Wizenmann  ABähr  M Growth preferences of adult rat retinal ganglion cell axons in retinotectal cocultures. J Neurobiol 1998;35 (4) 379- 387
PubMed
90.
Keirstead  SARasminsky  MFukuda  YCarter  DAAguayo  AJVidal-Sanz  M Electrophysiologic responses in hamster superior colliculus evoked by regenerating retinal axons. Science 1989;246 (4927) 255- 257
PubMed
91.
Steward  OZheng  BTessier-Lavigne  M False resurrections: distinguishing regenerated from spared axons in the injured central nervous system. J Comp Neurol 2003;459 (1) 1- 8
PubMed
Mechanisms of Ophthalmic Disease
August 2010

Optic Nerve Regeneration

Author Affiliations

Author Affiliations: Laboratories for Neuroscience Research in Neurosurgery, F.M. Kirby Neurobiology Center, Children's Hospital Boston, and Program in Neuroscience and Department of Surgery, Harvard Medical School, Boston, Massachusetts.

 

LEONARD A.LEVINMD, PhD

Arch Ophthalmol. 2010;128(8):1059-1064. doi:10.1001/archophthalmol.2010.152
Abstract

Retinal ganglion cells are usually not able to regenerate their axons after optic nerve injury or degenerative disorders, resulting in lifelong visual loss. This situation can be partially reversed by activating the intrinsic growth state of retinal ganglion cells, maintaining their viability, and counteracting inhibitory signals in the extracellular environment. Advances during the past few years continue to extend the amount of regeneration that can be achieved in animal models. These findings give hope that clinically meaningful regeneration may become a reality within a few years if regenerating axons can be guided to their appropriate destinations.

As in most central nervous system pathways, axons injured in the mature optic nerve cannot grow back, leaving patients who have traumatic nerve injury or degenerative diseases (such as glaucoma) with lifelong vision loss. Researchers have long studied the optic nerve for insights into the causes of regenerative failure in the central nervous system, focusing on such issues as the inhibitory effects of central nervous system myelin and the glial scar, the absence of appropriate trophic factors, the immune response to injury, cell-death pathways, and the decline in the intrinsic growth capacity of neurons. The past 10 to 15 years have witnessed major advances in understanding the reasons retinal ganglion cells (RGCs) normally fail to regenerate injured axons through the optic nerve and devising ways to reverse this situation. These findings give hope that functional repair might be possible.

AXON REGENERATION THROUGH THE OPTIC NERVE

Under normal circumstances, damaged axons show a transient sprouting response after optic nerve injury but no long-distance regeneration. Tello, a student of Ramon y Cajal,1 discovered that if the optic nerve is cut and sutured to a segment of peripheral nerve (PN), axons will grow for considerable distances into the graft. Aguayo et al2 extended these findings to show that some RGCs can regenerate axons all the way through a PN graft that extends from the eye to the superior colliculus and form synapses in the correct retinal recipient layers of the colliculus.

The ability of RGCs to regenerate axons through a PN graft is likely to be related in part to higher levels of growth-permissive molecules (eg, laminin) and lower levels of growth-inhibitory molecules (eg, Nogo-A) in PNs compared with the optic nerve.35 However, it is also possible that the optic nerve and PNs differ in their ability to provide essential trophic factors. To test this latter possibility, Berry and colleagues6 implanted a fragment of PN into the vitreous humor and found that this procedure stimulated RGCs to regenerate lengthy axons beyond the site of an optic nerve crush injury. Although this growth was initially attributed to trophic factors derived from Schwann cells, the grafts contained numerous macrophages, which can enhance axon regeneration when preactivated and placed in the optic nerve.7,8 Other methods that induce intraocular inflammation (ie, injuring the lens or injecting the proinflammatory agent zymosan into the eye) stimulate even greater regeneration than that stimulated by PN implants (Figure, A and B).9,10,14 This regeneration is associated with a marked change in the intrinsic growth state of RGCs, as evidenced by a marked upregulation of proteins such as GAP-43 and SPRR1A.13 Although PN implants secrete ciliary neurotrophic factor (CNTF),15 their primary effect in vivo is related to other factors associated with macrophages.16

ONCOMODULIN AS A POTENT MACROPHAGE-DERIVED GROWTH FACTOR FOR RGCs

Using dissociated retinal cell cultures as a bioassay, 2 molecules present in the eye were found to stimulate mature RGCs to regenerate their axons. One is mannose, a simple sugar that is abundant in the vitreous. Mannose stimulates RGCs to extend moderately long axons if cells have sufficiently high levels of intracellular cyclic adenosine monophosphate (cAMP).17 The second growth factor is oncomodulin (Ocm), a 12-kDa, calcium-binding protein secreted by macrophages. Oncomodulin accumulates rapidly in the eye after intravitreal inflammation and exhibits cAMP-dependent, high-affinity binding to a cell surface receptor on RGCs.11,12 When released from polymeric beads placed into the vitreous, Ocm plus a cAMP analogue induce nearly as much optic nerve axon regeneration as intraocular inflammation11 (Figure, C). Conversely, an Ocm peptide antagonist or a neutralizing antiOcm antibody markedly suppresses inflammation-induced regeneration (Figure, D).12 Thus, Ocm appears to mediate most of the effect of intravitreal inflammation on optic nerve regeneration. However, additional factors derived from inflammatory cells or retinal glia also appear to play a role by causing an elevation of intracellular cAMP and by enhancing RGC survival.12 One group failed to detect an elevation of Ocm in the eye after inflammation18 and reported that an anti-Ocm antibody did not diminish inflammation-induced regeneration.19 The likely sources of these discrepant results are discussed elsewhere.12,20 Intraocular inflammation also enhances the ability of RGCs to regenerate their axons through a PN graft,10,21 and this effect is likewise blocked by an Ocm antagonist peptide.12

ALTERING INTRACELLULAR SIGNALING CAN PROMOTE OPTIC NERVE REGENERATION

The signaling pathways that enable RGCs to regenerate their axons are beginning to emerge. The purine-sensitive protein kinase Mst3b plays a central role in the signal transduction pathway through which trophic factors induce axon growth.22,23 Suppression of Mst3b expression blocks the axon-promoting effects of Ocm in culture and of inflammation-induced regeneration in vivo,23 whereas expression of a constitutively active form of Mst3b enables RGCs to regenerate axons even in the absence of growth factors.23 The effects of Ocm can also be blocked by an inhibitor of calmodulin kinases or by combining inhibitors of the phosphatidylinositol 3-kinase, mitogen-activated protein kinases, and Janus kinase-signal transducer and activator of transcription pathways.11 Conversely, deleting genes that encode suppressors of these pathways stimulates axon regeneration in vivo. Appreciable optic nerve regeneration can be stimulated by deleting the gene for phosphatase and tensin homolog (PTEN), a protein and lipid phosphatase that suppresses signaling through the phosphatidylinositol 3-kinase–Akt pathway,24and, to a somewhat lesser extent, by deleting the gene encoding SOCS3, a protein that suppresses signaling through the Janus kinase-signal transducer and activator of transcription pathway.25 Deletion of PTEN or SOCS3 leads to phosphorylation of the S6 kinase, implying that activation of the mammalian target of rapamycin pathway plays an important role.

The intrinsic growth capacity of RGCs decreases in the early postnatal period26 and is accompanied by changes in the expression of Kruppel-like family (KLF) transcription factors. Overexpression of KLF-4 suppresses axon growth in immature RGCs, whereas diminished KLF-4 expression increases axon growth in mature RGCs and promotes a modest amount of regeneration in vivo.27 It is not yet known whether the effects of intraocular inflammation, PTEN deletion, or SOCS3 deletion are mediated through changes in the expression of any KLF transcription factors or whether manipulating multiple KLF members at once might produce more marked regeneration.

THE ROLE OF cAMP IN OPTIC NERVE REGENERATION

The second messenger cAMP augments axon regeneration in multiple ways, including altering the response of growth cones to inhibitory signals,28,29 stimulating the translocation of growth factor receptors to the cell surface,11,30 and altering gene expression programs.31 The latter effects include downregulation of SOCS3 expression32 and upregulation of arginase I,31 an enzyme involved in the biosynthesis of polyamines, which enhance the ability of neurons to extend axons over inhibitory substrates.31 Spermidine stimulates a modest amount of optic nerve regeneration,33 as does elevation of cAMP.11,34,35 As noted herein, cAMP strongly enhances the effects of oncomodulin11 and increases the effects of intraocular inflammation.36 A peptide that prevents Ocm from binding to its receptor eliminates the latter effects, showing that Ocm is the principal factor involved in inflammation-induced regeneration and in the enhancement of this phenomenon by cAMP.37

RGC SURVIVAL AFTER OPTIC NERVE INJURY

A few days after their axons are injured, RGCs begin to die, particularly if damage occurs close to the eye.38 This death can be prevented almost completely by overexpressing the antiapoptotic Bcl family proteins Bcl-2 or Bcl-xL in RGCs.39,40 However, although axon regeneration clearly requires RGCs to remain viable, axon outgrowth and cell survival use different intracellular signaling pathways. This dissociation is exemplified by the failure of RGCs overexpressing Bcl-2 or Bcl-xL to regenerate axons without additional growth factors39,41 and by the persistent enhancement of RGC survival seen after intraocular inflammation even when regeneration is suppressed by Ocm-blocking reagents.12

The death of RGCs can be slowed but not stopped with a number of trophic factors, including CNTF,35,42,43 BDNF,42,44,45 neurotrophin 4/5,46,47 nerve growth factor,48 insulinlike growth factor 1,49 granulocyte colony-stimulating factor,50 glial-derived neurotrophic factor,51,52 and neurturin.53 When BDNF is combined with glial-derived neurotrophic factor, neurturin, or intraocular inflammation, it has additive effects on survival, although the combination of BDNF and intraocular inflammation suppresses axon regeneration.53,54

The death of axotomized RGCs can be slowed by preventing caspase cleavage,5558 blocking the nuclear enzyme poly(adenosine diphosphate–ribose) polymerase (a substrate for caspases),59 blocking nitric oxide synthase,60 introducing reducing agents,61 or inhibiting cell death via caspase-independent pathways.6264 Long-term prevention of RGC death after axotomy may require the development of long-term delivery systems or a combination of treatments.

EFFECTS OF OTHER TROPHIC FACTORS ON OPTIC NERVE REGENERATION

Fibroblast growth factor 2 stimulates some axon regeneration through the optic nerve.65 However, nerve growth factor, neurotrophin 3, BDNF, and neurotrophin 4/5 do not,66,67 although a combination of fibroblast growth factor 2, neurotrophin 3, and nerve growth factor has been reported to induce substantial regeneration.67 One group has argued that CNTF mediates the effects of intravitreal inflammation on optic nerve regeneration. This observation is based primarily on the outgrowth seen using concentrations of CNTF several orders of magnitude above the established median effective dose in culture and on the loss of axon regeneration and RGC survival seen when the genes encoding CNTF and leukemia inhibitory factor are deleted.19,36,68 However, physiologically relevant concentrations of CNTF do not promote strong regeneration in culture9,11,12,46; many laboratories have failed to find strong effects of CNTF in vivo.9,25,43,54,69 In addition, CNTF inhibitors have no effect9,70 or only a mild effect19 on inflammation-induced regeneration. Although CNTF enhances axon regeneration through a PN graft,35,71 this effect is associated with the proinflammatory effects of high CNTF concentrations and is eliminated when inflammation is suppressed.72 Thus, the direct effect of CNTF on optic nerve regeneration is weak, although it may contribute to maintaining RGC survival. The axon-promoting effect of CNTF becomes strong when the gene that encodes SOCS3, the negative regulator of the Janus kinase-signal transducer and activator of transcription pathway, is deleted.25 However, optic nerve injury leads to an upregulation of SOCS3 in RGCs,13 which may help explain why axotomized RGCs show so little response to CNTF.9,25,43,54,69 Intraocular inflammation amplifies axotomy-induced SOCS upregulation greatly,13 further limiting any possible contribution of CNTF to inflammation-induced regeneration.20

GROWTH-INHIBITORY SIGNALS IN THE OPTIC NERVE

The mature optic nerve contains many molecules that suppress axon growth, including the myelin-associated inhibitors Nogo-A, myelin-associated glycoprotein, and oligodendrocyte-myelin glycoprotein; proteoglycans that accumulate in the scar at the injury site; and additional axon repellants (eg, semaphorins).7377 Methods that counteract Nogo-A signaling do not lead to appreciable optic nerve regeneration on their own.78 However, expression of a dominant-negative form of the Nogo receptor strongly amplifies the axon-promoting effects of intraocular inflammation.79 A more comprehensive way to counteract inhibition is by inactivating the small guanosine triphosphate hydrolase Ras homolog member A (RhoA), a part of the intracellular pathway through which multiple signals inhibit axon growth. Inhibition of RhoA results in modest levels of axon regeneration in the injured optic nerve80,81 but greatly increases the amount of regeneration associated with intraocular inflammation13 (Figure, E). Thus, although counteracting inhibitory signals is not sufficient to induce extensive optic nerve regeneration, treatments that simultaneously activate the growth state of RGCs and counteract inhibition can have notable effects.

Transforming RGCs into an active growth state enables axons to partially overcome inhibitory signals. The scar that forms at the injury site contains basement membrane components82 that are partially degraded by matrix metalloproteinases associated with growing axons.83 However, as noted herein, multiple other inhibitory signals remain in place, as evidenced by the notable effects seen when RhoA activity is suppressed in actively growing axons.

AXON GUIDANCE CUES DURING DEVELOPMENT AND REGENERATION

The initial development of retinal projections involves multiple cues that guide axons through the retina, optic disc, optic nerve, optic chiasm, diencephalon, and midbrain and enable them to form a topographically organized representation of visual space on central target areas. The guidance of retinal axons during development involves many types of axon-guidance molecules, including netrins, semaphorins, laminin, multiple members of the erythropoietin-producing hepatocellular (Eph) receptor/Eph receptor–interacting protein (ephrin) families, the developmental protein Wnt, and slits.8486 Because of the complex guidance mechanisms involved in the development of retinal projections, it will be important to determine whether the appropriate guidance cues are expressed in the mature brain to guide regenerating axons back to their correct destinations. There is evidence that at least some guidance cues remain in the mature central nervous system or become upregulated after optic nerve damage.8789 However, whether these cues will suffice to guide regenerating axons to their proper target areas and re-form topographically organized maps remains to be determined.

ARE WE THERE YET?

In studies using the PN graft model, anterograde tracing and electrophysiologic responses reveal that a small number of axons can regenerate all the way back to the superior colliculus.90 In the case of axon regeneration through the optic nerve, one group reported a remapping of the retina on the superior colliculus,14 but the accompanying histologic findings raised questions as to whether the axons had been severed in the first place. Because of the scientific and clinical importance of successful regeneration, it will be important to apply strict criteria to proving one's case, eg, showing that connections are forming gradually as time passes and are not owing to spared axons,91 and that any observed electrophysiologic changes correlate with clear anatomical evidence of regeneration. Despite these issues, the advances that have occurred during the past few years give hope for the possibility that at least some RGCs will be able to regenerate their axons all the way to their central targets. The next challenges will include finding ways to optimize this regeneration and testing whether they restore functionally meaningful levels of vision.

Back to top
Article Information

Correspondence: Larry I. Benowitz, PhD, CLS 13071, Children's Hospital Boston, 300 Longwood Ave, Boston, MA 02115 (larry.benowitz@childrens.harvard.edu).

Submitted for Publication: December 21, 2009; accepted February 18, 2010.

Financial Disclosure: None reported.

Funding/Support: This study was supported by grant EY05690 to Dr Benowitz from the National Eye Institute of the National Institutes of Health, the Sheldon and Miriam Adelson Medical Research Foundation, and Alseres Pharmaceuticals Inc.

References
1.
Ramon y Cajal  S  Degeneration and Regeneration of the Nervous System.  Vol 5. New York, NY Oxford University Press1991;
2.
Aguayo  AJRasminsky  MBray  GM  et al.  Degenerative and regenerative responses of injured neurons in the central nervous system of adult mammals. Philos Trans R Soc Lond B Biol Sci 1991;331 (1261) 337- 343
PubMed
3.
Carbonetto  SEvans  DCochard  P Nerve fiber growth in culture on tissue substrata from central and peripheral nervous systems. J Neurosci 1987;7 (2) 610- 620
PubMed
4.
Savio  TSchwab  ME Rat CNS white matter, but not gray matter, is nonpermissive for neuronal cell adhesion and fiber outgrowth. J Neurosci 1989;9 (4) 1126- 1133
PubMed
5.
Schwab  METhoenen  H Dissociated neurons regenerate into sciatic but not optic nerve explants in culture irrespective of neurotrophic factors. J Neurosci 1985;5 (9) 2415- 2423
PubMed
6.
Berry  MCarlile  JHunter  A Peripheral nerve explants grafted into the vitreous body of the eye promote the regeneration of retinal ganglion cell axons severed in the optic nerve. J Neurocytol 1996;25 (2) 147- 170
PubMed
7.
Lazarov-Spiegler  OSolomon  ASZeev-Brann  ABHirschberg  DLLavie  VSchwartz  M Transplantation of activated macrophages overcomes central nervous system regrowth failure. FASEB J 1996;10 (11) 1296- 1302
PubMed
8.
Lazarov-Spiegler  OSolomon  ASSchwartz  M Peripheral nerve-stimulated macrophages simulate a peripheral nerve-like regenerative response in rat transected optic nerve. Glia 1998;24 (3) 329- 337
PubMed
9.
Leon  SYin  YNguyen  JIrwin  NBenowitz  LI Lens injury stimulates axon regeneration in the mature rat optic nerve. J Neurosci 2000;20 (12) 4615- 4626
PubMed
10.
Yin  YCui  QLi  Y  et al.  Macrophage-derived factors stimulate optic nerve regeneration. J Neurosci 2003;23 (6) 2284- 2293
PubMed
11.
Yin  YHenzl  MTLorber  B  et al.  Oncomodulin is a macrophage-derived signal for axon regeneration in retinal ganglion cells. Nat Neurosci 2006;9 (6) 843- 852
PubMed
12.
Yin  YCui  QGilbert  H  et al.  Oncomodulin links inflammation to optic nerve regeneration. Proc Natl Acad Sci U S A 2009;106 (46) 19587- 19592
PubMed
13.
Fischer  DPetkova  VThanos  SBenowitz  LI Switching mature retinal ganglion cells to a robust growth state in vivo: gene expression and synergy with RhoA inactivation. J Neurosci 2004;24 (40) 8726- 8740
PubMed
14.
Fischer  DHeiduschka  PThanos  S Lens-injury-stimulated axonal regeneration throughout the optic pathway of adult rats. Exp Neurol 2001;172 (2) 257- 272
PubMed
15.
Jo  SWang  EBenowitz  LI Ciliary neurotrophic factor is an axogenesis factor for retinal ganglion cells. Neuroscience 1999;89 (2) 579- 591
PubMed
16.
Lorber  BBerry  MLogan  A Different factors promote axonal regeneration of adult rat retinal ganglion cells after lens injury and intravitreal peripheral nerve grafting. J Neurosci Res 2008;86 (4) 894- 903
PubMed
17.
Li  YIrwin  NYin  YLanser  MBenowitz  LI Axon regeneration in goldfish and rat retinal ganglion cells: differential responsiveness to carbohydrates and cAMP. J Neurosci 2003;23 (21) 7830- 7838
PubMed
18.
Hauk  TGMüller  ALee  JSchwendener  RFischer  D Neuroprotective and axon growth promoting effects of intraocular inflammation do not depend on oncomodulin or the presence of large numbers of activated macrophages. Exp Neurol 2008;209 (2) 469- 482
PubMed
19.
Müller  AHauk  TGFischer  D Astrocyte-derived CNTF switches mature RGCs to a regenerative state following inflammatory stimulation. Brain 2007;130 (pt 12) 3308- 3320
PubMed
20.
Cui  QBenowitz  LYin  Y Does CNTF mediate the effect of intraocular inflammation on optic nerve regeneration? Brain 2008;131 (pt 6) e96- e97
PubMed10.1093/brain/awn027
21.
Fischer  DPavlidis  MThanos  S Cataractogenic lens injury prevents traumatic ganglion cell death and promotes axonal regeneration both in vivo and in culture. Invest Ophthalmol Vis Sci 2000;41 (12) 3943- 3954
PubMed
22.
Irwin  NLi  Y-MO’Toole  JEBenowitz  LI Mst3b, a purine-sensitive Ste20-like protein kinase, regulates axon outgrowth. Proc Natl Acad Sci U S A 2006;103 (48) 18320- 18325
PubMed
23.
Lorber  BHowe  MLBenowitz  LIIrwin  N Mst3b, an Ste20-like kinase, regulates axon regeneration in the mature CNS and PNS. Nat Neurosci 2009;12 (11) 1407- 1414
PubMed
24.
Park  KKLiu  KHu  Y  et al.  Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science 2008;322 (5903) 963- 966
PubMed
25.
Smith  PDSun  FPark  KK  et al.  SOCS3 deletion promotes optic nerve regeneration in vivo. Neuron 2009;64 (5) 617- 623
PubMed
26.
Goldberg  JLKlassen  MPHua  YBarres  BA Amacrine-signaled loss of intrinsic axon growth ability by retinal ganglion cells. Science 2002;296 (5574) 1860- 1864
PubMed
27.
Moore  DLBlackmore  MGHu  Y  et al.  KLF family members regulate intrinsic axon regeneration ability. Science 2009;326 (5950) 298- 301
PubMed
28.
Ming  G-LSong  H-JBerninger  BHolt  CETessier-Lavigne  MPoo  M-M cAMP-dependent growth cone guidance by netrin-1. Neuron 1997;19 (6) 1225- 1235
PubMed
29.
Song  HMing  GHe  Z  et al.  Conversion of neuronal growth cone responses from repulsion to attraction by cyclic nucleotides. Science 1998;281 (5382) 1515- 1518
PubMed
30.
Meyer-Franke  AWilkinson  GAKruttgen  A  et al.  Depolarization and cAMP elevation rapidly recruit TrkB to the plasma membrane of CNS neurons. Neuron 1998;21 (4) 681- 693
PubMed
31.
Cai  DDeng  KMellado  WLee  JRatan  RFilbin  M Arginase I and polyamines act downstream from cyclic AMP in overcoming inhibition of axonal growth MAG and myelin in vitro. Neuron 2002;35 (4) 711- 719
PubMed
32.
Park  KKHu  YMuhling  J  et al.  Cytokine-induced SOCS expression is inhibited by cAMP analogue: impact on regeneration in injured retina. Mol Cell Neurosci 2009;41 (3) 313- 324
PubMed
33.
Deng  KHe  HQiu  JLorber  BBryson  JBFilbin  MT Increased synthesis of spermidine as a result of upregulation of arginase I promotes axonal regeneration in culture and in vivo. J Neurosci 2009;29 (30) 9545- 9552
PubMed
34.
Monsul  NTGeisendorfer  ARHan  PJ  et al.  Intraocular injection of dibutyryl cyclic AMP promotes axon regeneration in rat optic nerve. Exp Neurol 2004;186 (2) 124- 133
PubMed
35.
Cui  QYip  HKZhao  RCHSo  K-FHarvey  AR Intraocular elevation of cyclic AMP potentiates ciliary neurotrophic factor-induced regeneration of adult rat retinal ganglion cell axons. Mol Cell Neurosci 2003;22 (1) 49- 61
PubMed
36.
Müller  AHauk  TGLeibinger  MMarienfeld  RFischer  D Exogenous CNTF stimulates axon regeneration of retinal ganglion cells partially via endogenous CNTF. Mol Cell Neurosci 2009;41 (2) 233- 246
PubMed
37.
Yin  YKurimoto  TCen  LGilbert  HYang  YBenowitz  LI  Oncomodulin and cAMP interact in multiple ways to promote optic nerve regeneration.  Program and abstracts of the Society for Neuroscience Annual Meeting October 17-21, 2009 Chicago, IllinoisProgram 32.11
38.
Villegas-Pérez  MPVidal-Sanz  MBray  GMAguayo  AJ Influences of peripheral nerve grafts on the survival and regrowth of axotomized retinal ganglion cells in adult rats. J Neurosci 1988;8 (1) 265- 280
PubMed
39.
Chierzi  SCenni  MCMaffei  L  et al.  Protection of retinal ganglion cells and preservation of function after optic nerve lesion in bcl-2 transgenic mice. Vision Res 1998;38 (10) 1537- 1543
PubMed
40.
Malik  JMIShevtsova  ZBähr  MKügler  S Long-term in vivo inhibition of CNS neurodegeneration by Bcl-XL gene transfer. Mol Ther 2005;11 (3) 373- 381
PubMed
41.
Goldberg  JLEspinosa  JSXu  YDavidson  NKovacs  GTABarres  BA Retinal ganglion cells do not extend axons by default: promotion by neurotrophic signaling and electrical activity. Neuron 2002;33 (5) 689- 702
PubMed
42.
Mey  JThanos  S Intravitreal injections of neurotrophic factors support the survival of axotomized retinal ganglion cells in adult rats in vivo. Brain Res 1993;602 (2) 304- 317
PubMed
43.
Weise  JIsenmann  SKlöcker  N  et al.  Adenovirus-mediated expression of ciliary neurotrophic factor (CNTF) rescues axotomized rat retinal ganglion cells but does not support axonal regeneration in vivo. Neurobiol Dis 2000;7 (3) 212- 223
PubMed
44.
Mansour-Robaey  SClarke  DBWang  Y-CBray  GMAguayo  AJ Effects of ocular injury and administration of brain-derived neurotrophic factor on survival and regrowth of axotomized retinal ganglion cells. Proc Natl Acad Sci U S A 1994;91 (5) 1632- 1636
PubMed
45.
Di Polo  AAigner  LJDunn  RJBray  GMAguayo  AJ Prolonged delivery of brain-derived neurotrophic factor by adenovirus-infected Müller cells temporarily rescues injured retinal ganglion cells. Proc Natl Acad Sci U S A 1998;95 (7) 3978- 3983
PubMed
46.
Cohen  ABray  GMAguayo  AJ Neurotrophin-4/5 (NT-4/5) increases adult rat retinal ganglion cell survival and neurite outgrowth in vitro. J Neurobiol 1994;25 (8) 953- 959
PubMed
47.
Peinado-Ramón  PSalvador  MVillegas-Peréz  MPVidal-Sanz  M Effects of axotomy and intraocular administration of NT-4, NT-3, and brain-derived neurotrophic factor on the survival of adult rat retinal ganglion cells: a quantitative in vivo study. Invest Ophthalmol Vis Sci 1996;37 (4) 489- 500
PubMed
48.
Carmignoto  GMaffei  LCandeo  PCanella  RComelli  C Effect of NGF on the survival of rat retinal ganglion cells following optic nerve section. J Neurosci 1989;9 (4) 1263- 1272
PubMed
49.
Kermer  PKlöcker  NLabes  MBähr  M Insulin-like growth factor-I protects axotomized rat retinal ganglion cells from secondary death via PI3-K-dependent Akt phosphorylation and inhibition of caspase-3 In vivo. J Neurosci 2000;20 (2) 2- 8
PubMed
50.
Frank  TSchlachetzki  JCMGöricke  B  et al.  Both systemic and local application of granulocyte-colony stimulating factor (G-CSF) is neuroprotective after retinal ganglion cell axotomy. BMC Neurosci 2009;1049- 58
PubMed
51.
Koeberle  PDBall  AK Effects of GDNF on retinal ganglion cell survival following axotomy. Vision Res 1998;38 (10) 1505- 1515
PubMed
52.
Yan  QWang  JMatheson  CRUrich  JL Glial cell line-derived neurotrophic factor (GDNF) promotes the survival of axotomized retinal ganglion cells in adult rats: comparison to and combination with brain-derived neurotrophic factor (BDNF). J Neurobiol 1999;38 (3) 382- 390
PubMed
53.
Koeberle  PDBall  AK Neurturin enhances the survival of axotomized retinal ganglion cells in vivo: combined effects with glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor. Neuroscience 2002;110 (3) 555- 567
PubMed
54.
Pernet  VDi Polo  A Synergistic action of brain-derived neurotrophic factor and lens injury promotes retinal ganglion cell survival, but leads to optic nerve dystrophy in vivo. Brain 2006;129 (pt 4) 1014- 1026
PubMed
55.
Kermer  PKlöcker  NLabes  MBähr  M Inhibition of CPP32-like proteases rescues axotomized retinal ganglion cells from secondary cell death in vivo. J Neurosci 1998;18 (12) 4656- 4662
PubMed
56.
Kermer  PKlöcker  NBähr  M Long-term effect of inhibition of ced 3-like caspases on the survival of axotomized retinal ganglion cells in vivo. Exp Neurol 1999;158 (1) 202- 205
PubMed
57.
Kermer  PAnkerhold  RKlöcker  NKrajewski  SReed  JCBähr  M Caspase-9: involvement in secondary death of axotomized rat retinal ganglion cells in vivo. Brain Res Mol Brain Res 2000;85 (1-2) 144- 150
PubMed
58.
Weishaupt  JHDiem  RKermer  PKrajewski  SReed  JCBähr  M Contribution of caspase-8 to apoptosis of axotomized rat retinal ganglion cells in vivo. Neurobiol Dis 2003;13 (2) 124- 135
PubMed
59.
Weise  JIsenmann  SBähr  M Increased expression and activation of poly(ADP-ribose) polymerase (PARP) contribute to retinal ganglion cell death following rat optic nerve transection. Cell Death Differ 2001;8 (8) 801- 807
PubMed
60.
Koeberle  PDBall  AK Nitric oxide synthase inhibition delays axonal degeneration and promotes the survival of axotomized retinal ganglion cells. Exp Neurol 1999;158 (2) 366- 381
PubMed
61.
Swanson  KISchlieve  CRLieven  CJLevin  LA Neuroprotective effect of sulfhydryl reduction in a rat optic nerve crush model. Invest Ophthalmol Vis Sci 2005;46 (10) 3737- 3741
PubMed
62.
Sanders  EJParker  EHarvey  S Retinal ganglion cell survival in development: mechanisms of retinal growth hormone action. Exp Eye Res 2006;83 (5) 1205- 1214
PubMed
63.
Cheung  ZHLeung  MCPYip  HKWu  WSiu  FKWSo  K-F A neuroprotective herbal mixture inhibits caspase-3-independent apoptosis in retinal ganglion cells. Cell Mol Neurobiol 2008;28 (1) 137- 155
PubMed
64.
Fitzgerald  MPayne  SCBartlett  CAEvill  LHarvey  ARDunlop  SA Secondary retinal ganglion cell death and the neuroprotective effects of the calcium channel blocker lomerizine. Invest Ophthalmol Vis Sci 2009;50 (11) 5456- 5462
PubMed
65.
Sapieha  PSPeltier  MRendahl  KGManning  WCDi Polo  A Fibroblast growth factor-2 gene delivery stimulates axon growth by adult retinal ganglion cells after acute optic nerve injury. Mol Cell Neurosci 2003;24 (3) 656- 672
PubMed
66.
Cui  QLu  QSo  KFYip  HK CNTF, not other trophic factors, promotes axonal regeneration of axotomized retinal ganglion cells in adult hamsters. Invest Ophthalmol Vis Sci 1999;40 (3) 760- 766
PubMed
67.
Logan  AAhmed  ZBaird  AGonzalez  AMBerry  M Neurotrophic factor synergy is required for neuronal survival and disinhibited axon regeneration after CNS injury. Brain 2006;129 (pt 2) 490- 502
PubMed
68.
Leibinger  MMüller  AAndreadaki  AHauk  TGKirsch  MFischer  D Neuroprotective and axon growth-promoting effects following inflammatory stimulation on mature retinal ganglion cells in mice depend on ciliary neurotrophic factor and leukemia inhibitory factor. J Neurosci 2009;29 (45) 14334- 14341
PubMed
69.
Lingor  PTönges  LPieper  N  et al.  ROCK inhibition and CNTF interact on intrinsic signalling pathways and differentially regulate survival and regeneration in retinal ganglion cells. Brain 2008;131 (pt 1) 250- 263
PubMed
70.
Lorber  BBerry  MLogan  ATonge  D Effect of lens lesion on neurite outgrowth of retinal ganglion cells in vitro. Mol Cell Neurosci 2002;21 (2) 301- 311
PubMed
71.
Cui  QHarvey  AR CNTF promotes the regrowth of retinal ganglion cell axons into murine peripheral nerve grafts. Neuroreport 2000;11 (18) 3999- 4002
PubMed
72.
Cen  L-PLuo  J-MZhang  C-W  et al.  Chemotactic effect of ciliary neurotrophic factor on macrophages in retinal ganglion cell survival and axonal regeneration. Invest Ophthalmol Vis Sci 2007;48 (9) 4257- 4266
PubMed
73.
Filbin  MT Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS. Nat Rev Neurosci 2003;4 (9) 703- 713
PubMed
74.
Cafferty  WBJ McGee  AWStrittmatter  SM Axonal growth therapeutics: regeneration or sprouting or plasticity? Trends Neurosci 2008;31 (5) 215- 220
PubMed
75.
Rossignol  SSchwab  MSchwartz  MFehlings  MG Spinal cord injury: time to move? J Neurosci 2007;27 (44) 11782- 11792
PubMed
76.
Silver  JMiller  JH Regeneration beyond the glial scar. Nat Rev Neurosci 2004;5 (2) 146- 156
PubMed
77.
Goldberg  JLVargas  MEWang  JT  et al.  An oligodendrocyte lineage-specific semaphorin, Sema5A, inhibits axon growth by retinal ganglion cells. J Neurosci 2004;24 (21) 4989- 4999
PubMed
78.
Chierzi  SStrettoi  ECenni  MCMaffei  L Optic nerve crush: axonal responses in wild-type and bcl-2 transgenic mice. J Neurosci 1999;19 (19) 8367- 8376
PubMed
79.
Fischer  DHe  ZBenowitz  LI Counteracting the Nogo receptor enhances optic nerve regeneration if retinal ganglion cells are in an active growth state. J Neurosci 2004;24 (7) 1646- 1651
PubMed
80.
Lehmann  MFournier  ASelles-Navarro  I  et al.  Inactivation of Rho signaling pathway promotes CNS axon regeneration. J Neurosci 1999;19 (17) 7537- 7547
PubMed
81.
Bertrand  JWinton  MJRodriguez-Hernandez  NCampenot  RB McKerracher  L Application of Rho antagonist to neuronal cell bodies promotes neurite growth in compartmented cultures and regeneration of retinal ganglion cell axons in the optic nerve of adult rats. J Neurosci 2005;25 (5) 1113- 1121
PubMed
82.
Battisti  WPShinar  YSchwartz  MLevitt  PMurray  M Temporal and spatial patterns of expression of laminin, chondroitin sulphate proteoglycan and HNK-1 immunoreactivity during regeneration in the goldfish optic nerve. J Neurocytol 1992;21 (8) 557- 573
PubMed
83.
Ahmed  ZDent  RGLeadbeater  WESmith  CBerry  MLogan  A Matrix metalloproteases: degradation of the inhibitory environment of the transected optic nerve and the scar by regenerating axons. Mol Cell Neurosci 2005;28 (1) 64- 78
PubMed
84.
Haupt  CHuber  AB How axons see their way: axonal guidance in the visual system. Front Biosci 2008;133136- 3149
PubMed
85.
Erskine  LHerrera  E The retinal ganglion cell axon's journey: insights into molecular mechanisms of axon guidance. Dev Biol 2007;308 (1) 1- 14
PubMed
86.
McLaughlin  TO’Leary  DD Molecular gradients and development of retinotopic maps. Annu Rev Neurosci 2005;28327- 355
PubMed
87.
Wizenmann  AThies  EKlostermann  SBonhoeffer  FBähr  M Appearance of target-specific guidance information for regenerating axons after CNS lesions. Neuron 1993;11 (5) 975- 983
PubMed
88.
Bähr  MWizenmann  A Retinal ganglion cell axons recognize specific guidance cues present in the deafferented adult rat superior colliculus. J Neurosci 1996;16 (16) 5106- 5116
PubMed
89.
Wizenmann  ABähr  M Growth preferences of adult rat retinal ganglion cell axons in retinotectal cocultures. J Neurobiol 1998;35 (4) 379- 387
PubMed
90.
Keirstead  SARasminsky  MFukuda  YCarter  DAAguayo  AJVidal-Sanz  M Electrophysiologic responses in hamster superior colliculus evoked by regenerating retinal axons. Science 1989;246 (4927) 255- 257
PubMed
91.
Steward  OZheng  BTessier-Lavigne  M False resurrections: distinguishing regenerated from spared axons in the injured central nervous system. J Comp Neurol 2003;459 (1) 1- 8
PubMed
×