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PMID: 23349896 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

The insulin-like growth factor 1 receptor is essential for axonal regeneration in adult central nervous system neurons.

PloS one ·Vol. 8 ·No. 1 ·2013-00-00 ·Pages e54462

Dupraz S, Grassi D, Karnas D, Nieto Guil AF, Hicks D, Quiroga S

Abstract

Axonal regeneration is an essential condition to re-establish functional neuronal connections in the injured adult central nervous system (CNS), but efficient regrowth of severed axons has proven to be very difficult to achieve. Although significant progress has been made in identifying the intrinsic and extrinsic mechanisms involved, many aspects remain unresolved. Axonal development in embryonic CNS (hippocampus) requires the obligate activation of the insulin-like growth factor 1 receptor (IGF-1R). Based on known similarities between axonal growth in fetal compared to mature CNS, we decided to examine the expression of the IGF-1R, using an antibody to the βgc subunit or a polyclonal anti-peptide antibody directed to the IGF-R (C20), in an in vitro model of adult CNS axonal regeneration, namely retinal ganglion cells (RGC) derived from adult rat retinas. Expression of both βgc and the β subunit recognized by C20 antibody were low in freshly isolated adult RGC, but increased significantly after 4 days in vitro. As in embryonic axons, βgc was localised to distal regions and leading growth cones in RGC. IGF-1R-βgc co-localised with activated p85 involved in the phosphatidylinositol-3 kinase (PI3K) signaling pathway, upon stimulation with IGF-1. Blocking experiments using either an antibody which neutralises IGF-1R activation, shRNA designed against the IGF-1R sequence, or the PI3K pathway inhibitor LY294002, all significantly reduced axon regeneration from adult RGC in vitro (∼40% RGC possessed axons in controls vs 2-8% in the different blocking studies). Finally, co-transfection of RGC with shRNA to silence IGF-1R together with a vector containing a constitutively active form of downstream PI3K (p110), fully restored axonal outgrowth in vitro. Hence these data demonstrate that axonal regeneration in adult CNS neurons requires re-expression and activation of IGF-1R, and targeting this system may offer new therapeutic approaches to enhancing axonal regeneration following trauma.

MeSH Terms
Animals Axons/drug effects,metabolism,physiology Central Nervous System/drug effects,growth & development,metabolism Chromones/pharmacology Gene Expression Regulation Humans Insulin-Like Growth Factor I/metabolism Morpholines/pharmacology Neurons/cytology,metabolism Phosphatidylinositol 3-Kinases/metabolism Phosphoinositide-3 Kinase Inhibitors Rats Rats, Wistar Receptor, IGF Type 1/genetics,metabolism Regeneration/drug effects,physiology Retinal Ganglion Cells/metabolism,physiology Signal Transduction/drug effects Transcriptional Activation
Chemicals
Chromones Morpholines Phosphoinositide-3 Kinase Inhibitors 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one Insulin-Like Growth Factor I Receptor, IGF Type 1
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Dupraz Sebastián
Departamento de Química Biológica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba y Centro de Investigaciones en Química Biológica de Córdoba (CIQUIBIC), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina.
Grassi Diego
Karnas Diana
Nieto Guil Alvaro F
Hicks David
Quiroga Santiago
References (49)
49 references, click to expand
  1. Extracellular signal-regulated kinases 1/2 are required for adult retinal ganglion cell axon regeneration induced by fibroblast growth factor-2.
    J Neurosci Res. 2006 May 1;83(6):985-95 PMID: 16493686
  2. Actions of neurotrophic factors and their signaling pathways in neuronal survival and axonal regeneration.
    Mol Neurobiol. 2006 Apr;33(2):155-79 PMID: 16603794
  3. Hippocampal neuronal polarity specified by spatially localized mPar3/mPar6 and PI 3-kinase activity.
    Cell. 2003 Jan 10;112(1):63-75 PMID: 12526794
  4. New directions in neuroregeneration.
    Expert Opin Biol Ther. 2006 Aug;6(8):735-8 PMID: 16856795
  5. Traumatic optic neuropathy therapy: an update of clinical and experimental studies.
    J Int Med Res. 2008 Sep-Oct;36(5):883-9 PMID: 18831880
  6. The efficacy of small interfering RNAs targeted to the type 1 insulin-like growth factor receptor (IGF1R) is influenced by secondary structure in the IGF1R transcript.
    J Biol Chem. 2003 May 2;278(18):15991-7 PMID: 12604614
  7. Coordinate expression of insulin-like growth factor system components by neurons and neuroglia during retinal and cerebellar development.
    J Neurosci. 1992 Dec;12(12):4737-44 PMID: 1281494
  8. Intrinsic changes in developing retinal neurons result in regenerative failure of their axons.
    Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7287-91 PMID: 7638182
  9. Axon-glia interactions regulate ECM patterning in the postnatal rat olfactory bulb.
    J Neurosci. 1994 Oct;14(10):6121-31 PMID: 7523632
  10. Growth promoting and inhibitory effects of glial cells in the mammalian nervous system.
    Adv Exp Med Biol. 1999;468:199-205 PMID: 10635030
  11. Insulin-like growth factor I receptors of fetal brain are enriched in nerve growth cones and contain a beta-subunit variant.
    Proc Natl Acad Sci U S A. 1995 May 9;92(10):4309-12 PMID: 7753803
  12. PAR-6-PAR-3 mediates Cdc42-induced Rac activation through the Rac GEFs STEF/Tiam1.
    Nat Cell Biol. 2005 Mar;7(3):270-7 PMID: 15723051
  13. Adult retinal neuronal cell culture.
    Prog Retin Eye Res. 2007 Jul;26(4):379-97 PMID: 17482863
  14. Comparative study of the three neurofilament subunits within pig and human retinal ganglion cells.
    Mol Vis. 2004 Feb 10;10:83-92 PMID: 14961007
  15. Brain-derived neurotrophic factor signalling in adult pig retinal ganglion cell neurite regeneration in vitro.
    Brain Res. 2004 May 8;1007(1-2):142-51 PMID: 15064145
  16. A novel method to prepare highly enriched primary cultures of chicken retinal horizontal cells.
    Exp Eye Res. 2012 Aug;101:44-8 PMID: 22683948
  17. Insulin-like growth factor I partly prevents axon elimination in the neonate rat optic nerve.
    Neurosci Lett. 2002 Jun 14;325(3):207-10 PMID: 12044657
  18. Adeno-associated viral-mediated catalase expression suppresses optic neuritis in experimental allergic encephalomyelitis.
    Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13847-52 PMID: 9811889
  19. IGF-1 receptor is essential for the establishment of hippocampal neuronal polarity.
    Nat Neurosci. 2006 Aug;9(8):993-5 PMID: 16845384
  20. Localization of mRNAs for insulin-like growth factor-I (IGF-I), IGF-I receptor, and IGF binding proteins in rat eye.
    Invest Ophthalmol Vis Sci. 1996 Jun;37(7):1459-68 PMID: 8641849
  21. Expression and distribution of IGF-1 receptors containing a beta-subunit variant (betagc) in developing neurons.
    J Neurosci. 1997 Feb 15;17(4):1447-59 PMID: 9006986
  22. Extrinsic regulation of injury/growth-related gene expression in the inferior olive of the adult rat.
    Eur J Neurosci. 2003 Oct;18(8):2146-58 PMID: 14622175
  23. Insulin and insulinlike growth factor 1 (IGF-1) receptors during central nervous system development: expression of two immunologically distinct IGF-1 receptor beta subunits.
    Mol Cell Biol. 1989 Jul;9(7):2806-17 PMID: 2476658
  24. Increased ocular levels of IGF-1 in transgenic mice lead to diabetes-like eye disease.
    J Clin Invest. 2004 Apr;113(8):1149-57 PMID: 15085194
  25. Molecular mechanisms of axonal growth.
    Adv Exp Med Biol. 2007;621:1-16 PMID: 18269207
  26. IGF-I enhances neurite regeneration but is not required for its survival in adult DRG explant.
    Neuroreport. 1997 Jul 7;8(9-10):2265-9 PMID: 9243623
  27. Upregulation of IGF-I in the goldfish retinal ganglion cells during the early stage of optic nerve regeneration.
    Neurochem Int. 2007 Apr;50(5):749-56 PMID: 17363112
  28. Axonal regeneration in adult CNS neurons--signaling molecules and pathways.
    J Neurochem. 2006 Mar;96(6):1501-8 PMID: 16476081
  29. 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 Jan 15;20(2):2-8 PMID: 10632601
  30. Hepatocyte growth factor protects retinal ganglion cells by increasing neuronal survival and axonal regeneration in vitro and in vivo.
    J Neurochem. 2011 Jun;117(5):892-903 PMID: 21443522
  31. Ischemic optic neuropathy.
    Prog Retin Eye Res. 2009 Jan;28(1):34-62 PMID: 19063989
  32. Characterization of the signaling interactions that promote the survival and growth of developing retinal ganglion cells in culture.
    Neuron. 1995 Oct;15(4):805-19 PMID: 7576630
  33. IGF-I specifically enhances axon outgrowth of corticospinal motor neurons.
    Nat Neurosci. 2006 Nov;9(11):1371-81 PMID: 17057708
  34. PIP3 is involved in neuronal polarization and axon formation.
    J Neurochem. 2004 Apr;89(1):109-18 PMID: 15030394
  35. Early downregulation of IGF-I decides the fate of rat retinal ganglion cells after optic nerve injury.
    Neurochem Int. 2007 Apr;50(5):741-8 PMID: 17363111
  36. Molecular and cell-based approaches for neuroprotection in glaucoma.
    Optom Vis Sci. 2008 Jun;85(6):417-24 PMID: 18521011
  37. Possible involvement of a fibroblast growth factor 9 (FGF9)-FGF receptor-3-mediated pathway in adult pig retinal ganglion cell survival in vitro.
    Mol Cell Neurosci. 2003 May;23(1):39-53 PMID: 12799136
  38. Long-distance axon regeneration in the mature optic nerve: contributions of oncomodulin, cAMP, and pten gene deletion.
    J Neurosci. 2010 Nov 17;30(46):15654-63 PMID: 21084621
  39. Ras-dependent induction of cellular responses by constitutively active phosphatidylinositol-3 kinase.
    Science. 1995 Apr 7;268(5207):100-2 PMID: 7701328
  40. Intrinsic neuronal determinants that promote axonal sprouting and elongation.
    Bioessays. 1997 Sep;19(9):767-75 PMID: 9297967
  41. Can regenerating axons recapitulate developmental guidance during recovery from spinal cord injury?
    Nat Rev Neurosci. 2006 Aug;7(8):603-16 PMID: 16858389
  42. Neurite growth promotion by nerve growth factor and insulin-like growth factor-1 in cultured adult sensory neurons: role of phosphoinositide 3-kinase and mitogen activated protein kinase.
    J Neurosci Res. 2001 Mar 15;63(6):486-99 PMID: 11241584
  43. The relationship between neuronal survival and regeneration.
    Annu Rev Neurosci. 2000;23:579-612 PMID: 10845076
  44. Fibroblast growth factor-2 gene delivery stimulates axon growth by adult retinal ganglion cells after acute optic nerve injury.
    Mol Cell Neurosci. 2003 Nov;24(3):656-72 PMID: 14664816
  45. Insulin-like growth factor-I and its receptor in neovascular age-related macular degeneration.
    Invest Ophthalmol Vis Sci. 2003 May;44(5):2192-8 PMID: 12714661
  46. Axonal regeneration of retinal ganglion cells: effect of trophic factors.
    Prog Retin Eye Res. 2000 Sep;19(5):559-75 PMID: 10925243
  47. Regulation of intrinsic neuronal properties for axon growth and regeneration.
    Prog Neurobiol. 2007 Jan;81(1):1-28 PMID: 17234322
  48. Selective excitotoxic degeneration of adult pig retinal ganglion cells in vitro.
    Invest Ophthalmol Vis Sci. 2001 Apr;42(5):1096-106 PMID: 11274091
  49. Regulation of intrinsic regenerative properties and axonal plasticity in cerebellar Purkinje cells.
    Restor Neurol Neurosci. 2001;19(1-2):85-94 PMID: 12085795
Article Info
Journal
PloS one
Abbr.
PLoS One
ISSN
1932-6203
DOI
10.1371/journal.pone.0054462
Published
2013-00-00
Epub
2013-00-18
Pages
e54462
Language
English
Region
United States
NLM ID
101285081
PMCID
PMC3548777
Subset
IM
External Links
PubMed source DOI: 10.1371/journal.pone.0054462 PMC Full Text View journal details
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