title: Re-establishing the regenerative potential of central nervous system axons in postnatal mice.
abstract: At a certain point in development, axons in the mammalian central nervous system lose their ability to regenerate after injury. Using the optic nerve model, we show that this growth failure coincides with two developmental events: the loss of Bcl-2 expression by neurons and the maturation of astrocytes. Before postnatal day 4, when astrocytes are immature, overexpression of Bcl-2 alone supported robust and rapid optic nerve regeneration over long distances, leading to innervation of brain targets by day 4 in mice. As astrocytes matured after postnatal day 4, axonal regeneration was inhibited in mice overexpressing Bcl-2. Concurrent induction of Bcl-2 and attenuation of reactive gliosis reversed the failure of CNS axonal re-elongation in postnatal mice and led to rapid axonal regeneration over long distances and reinnervation of the brain targets by a majority of severed optic nerve fibers up to 2 weeks of age. These results suggest that an early postnatal downregulation of Bcl-2 and post-traumatic reactive gliosis are two important elements of axon regenerative failure in the CNS.
authors.affiliation: Schepens Eye Research Institute, Program in Neuroscience and Department of Ophthalmology, Harvard Medical School, 20 Staniford Street, Boston, MA 02114, USA.
authors.forename: Kin-Sang
authors.initials: KS
authors.lastname: Cho
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.forename: Bin
authors.initials: B
authors.lastname: Lu
authors.forename: Hong
authors.initials: H
authors.lastname: Feng Ma
authors.forename: Xizhong
authors.initials: X
authors.lastname: Huang
authors.forename: Milos
authors.initials: M
authors.lastname: Pekny
authors.forename: Dong Feng
authors.initials: DF
authors.lastname: Chen
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D001369:Axons / Q000378:metabolism*; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002490:Central Nervous System / Q000502:physiology*; D018920:Coculture Techniques; D017931:DNA Primers / Q000737:chemistry; D015536:Down-Regulation; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D008953:Models, Anatomic; D009416:Nerve Regeneration; D009474:Neurons / Q000378:metabolism; D009900:Optic Nerve / Q000033:anatomy & histology* / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism / Q000502:physiology*; D012160:Retina / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019076:Transgenes; D014746:Vimentin / Q000378:metabolism
chemical_list: D017931:DNA Primers; D005904:Glial Fibrillary Acidic Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D014746:Vimentin
references.citation: Curr Biol. 1997 Oct 1;7(10):798-800
references.pmid: 9368763
references.citation: Nature. 1997 Dec 18-25;390(6661):680-3
references.pmid: 9414159
references.citation: Brain Res Brain Res Rev. 1998 Mar;26(1):29-42
references.pmid: 9600623
references.citation: Curr Opin Neurobiol. 1998 Dec;8(6):800-7
references.pmid: 9914245
references.citation: Cell Death Differ. 1998 Oct;5(10):816-22
references.pmid: 10203691
references.citation: J Cell Biol. 1999 May 3;145(3):503-14
references.pmid: 10225952
references.citation: J Neurosci. 1999 Jul 15;19(14):5810-22
references.pmid: 10407022
references.citation: J Neurosci. 1999 Oct 1;19(19):8367-76
references.pmid: 10493738
references.citation: EMBO J. 2005 Mar 9;24(5):1068-78
references.pmid: 15719013
references.citation: Annu Rev Neurosci. 2000;23:579-612
references.pmid: 10845076
references.citation: Nature. 2000 Oct 26;407(6807):963-70
references.pmid: 11069169
references.citation: Neuroscience. 2000;101(2):451-8
references.pmid: 11074167
references.citation: Curr Opin Neurobiol. 2001 Feb;11(1):89-94
references.pmid: 11179877
references.citation: J Neurosci Res. 2001 Jan 15;63(2):109-15
references.pmid: 11169620
references.citation: Eur J Neurosci. 2001 Feb;13(4):833-8
references.pmid: 11207819
references.citation: Brain Res Brain Res Rev. 2001 Oct;36(2-3):204-12
references.pmid: 11690617
references.citation: Science. 2002 Jun 7;296(5574):1860-4
references.pmid: 12052959
references.citation: J Comp Neurol. 2002 Nov 18;453(3):292-304
references.pmid: 12378589
references.citation: Prog Brain Res. 2002;137:313-32
references.pmid: 12440375
references.citation: Invest Ophthalmol Vis Sci. 2003 Jan;44(1):347-54
references.pmid: 12506095
references.citation: Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1902-7
references.pmid: 12576554
references.citation: J Neurosci. 2003 Mar 15;23(6):2284-93
references.pmid: 12657687
references.citation: Trends Neurosci. 2003 Apr;26(4):193-8
references.pmid: 12689770
references.citation: J Neurocytol. 2002 Feb;31(2):93-120
references.pmid: 12815233
references.citation: Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):8999-9004
references.pmid: 12861073
references.citation: Nat Neurosci. 2003 Aug;6(8):863-8
references.pmid: 12845328
references.citation: J Neurosci. 2003 Aug 27;23(21):7783-8
references.pmid: 12944507
references.citation: Neuron. 2003 Sep 11;39(6):919-35
references.pmid: 12971893
references.citation: J Neurosci. 2004 May 26;24(21):5016-21
references.pmid: 15163694
references.citation: J Cell Sci. 2004 Jul 15;117(Pt 16):3481-8
references.pmid: 15226376
references.citation: J Pathol. 2004 Nov;204(4):428-37
references.pmid: 15495269
references.citation: Eur J Cell Biol. 1981 Jun;24(2):191-6
references.pmid: 7285936
references.citation: Annu Rev Biochem. 1982;51:219-50
references.pmid: 6180679
references.citation: Exp Brain Res. 1991;87(2):371-82
references.pmid: 1722759
references.citation: Histol Histopathol. 1986 Jul;1(3):271-5
references.pmid: 2485166
references.citation: Glia. 1992;6(2):138-48
references.pmid: 1398895
references.citation: Development. 1994 Feb;120(2):301-11
references.pmid: 8149910
references.citation: Neuron. 1994 Oct;13(4):1017-30
references.pmid: 7946326
references.citation: Cell. 1994 Nov 18;79(4):679-94
references.pmid: 7954832
references.citation: J Neurol. 1994 Dec;242(1 Suppl 1):S22-4
references.pmid: 7535345
references.citation: EMBO J. 1995 Apr 18;14(8):1590-8
references.pmid: 7737111
references.citation: Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7287-91
references.pmid: 7638182
references.citation: Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4504-8
references.pmid: 8633098
references.citation: Glia. 1996 Apr;16(4):351-8
references.pmid: 8721675
references.citation: J Neurosci. 1996 Jul 1;16(13):4186-94
references.pmid: 8753880
references.citation: Neurosci Lett. 1996 Jan 5;202(3):161-4
references.pmid: 8848256
references.citation: Nature. 1997 Jan 30;385(6615):434-9
references.pmid: 9009190
references.citation: Annu Rev Neurosci. 1997;20:245-67
references.pmid: 9056714