Excess Bcl-XL increases the intrinsic growth potential of adult CNS neurons in vitro.
The regenerative potential of adult mammalian CNS neurons is limited. Recent data suggest that inactivation of major growth inhibitors may not suffice to induce robust regeneration from mature neurons unless the intrinsic growth state is modulated. To investigate a possible role of Bcl-XL for axon regeneration in the adult mammalian CNS, Bcl-XL was adenovirally overexpressed in severed rat RGCs. Bcl-XL overexpression in mature axotomized RGCs in vivo increased both numbers [3.10-fold (+/-0.20)] and cumulative length [6.72-fold (+/-0.47)] of neurites regenerated from retinal explants, and this effect was further pronounced in the central retina where specific and dense axoplasmatic transduction occurs. Similarly, delayed Bcl-XL gene transfer to explanted retinae 12-13 days after lesion increased the numbers and length of emanating neurites by a factor of 5.22 (+/-0.41) and 8.29 (+/-0.69), respectively. In vivo, intraretinal sprouting of unmyelinated RGC axons into the nerve fiber layer was increased. However, fiber ingrowth into the optic nerve remained sparse, likely due to myelin inhibitors and scar components. Therefore, Bcl-XL overexpression may enhance, but may not be sufficient to, restitute functional regeneration in the adult CNS. As assessed by cell quantification analysis, Bcl-XL overexpression rescued a higher proportion of RGCs in vivo than in vitro. Therefore, Bcl-XL is capable to induce both neuronal survival and axon regeneration, but these two processes appear to be differentially modified by distinct pathways in vivo.
Kretz
Alexandra
A
Neuroregeneration Laboratory, Department of Neurology, University of Jena Medical School, Jena, Germany.
Kügler
Sebastian
S
Happold
Caroline
C
Bähr
Mathias
M
Isenmann
Stefan
S
D000818:Animals; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology / Q000378:metabolism; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D020439:Growth Cones / Q000378:metabolism* / Q000648:ultrastructure; D009416:Nerve Regeneration / Q000235:genetics*; D009473:Neuronal Plasticity / Q000235:genetics*; D009900:Optic Nerve / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics*; D051020:bcl-X Protein
C494813:Bcl2l1 protein, rat; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein