Re-establishing the regenerative potential of central nervous system axons in postnatal mice.
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.
Cho
Kin-Sang
KS
Schepens Eye Research Institute, Program in Neuroscience and Department of Ophthalmology, Harvard Medical School, 20 Staniford Street, Boston, MA 02114, USA.
Yang
Liu
L
Lu
Bin
B
Feng Ma
Hong
H
Huang
Xizhong
X
Pekny
Milos
M
Chen
Dong Feng
DF
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
D017931:DNA Primers; D005904:Glial Fibrillary Acidic Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D014746:Vimentin
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