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The Journal of Neuroscience, October 6, 2004, 24(40):8726-8740; doi:10.1523/JNEUROSCI.2774-04.2004
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Development/Plasticity/Repair
Switching Mature Retinal Ganglion Cells to a Robust Growth State In Vivo: Gene Expression and Synergy with RhoA Inactivation
Dietmar Fischer,1,2,4 Victoria Petkova,5 Solon Thanos,6 andLarry I. Benowitz1,2,3 1Laboratories for Neuroscience Research in Neurosurgery, Children's Hospital, Boston, Massachusetts 02115, 2Department of Surgery and 3Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115, 4Department of Experimental Neurology, University of Ulm, 89081 Ulm, Germany, 5TaqMan RT-PCR Core, Harvard Institutes of Medicine, Beth Israel-Deaconess Hospital, Boston, Massachusetts 02115, and 6Experimental Ophthalmology, Westfälische Wilhelms-University, D-48149 Münster, Germany
The inability of mature CNS neurons to regenerate injured axons has been attributed to a loss of inherent growth potential of cells and to inhibitory signals associated with myelin and the glial scar. The present study investigated two complementary issues: (1) whether mature CNS neurons can be stimulated to alter their gene expression profile and switch into a strong growth state; and (2) whether inactivating RhoA, a convergence point for multiple inhibitory signals, is sufficient to produce strong regeneration even without activating the growth state of neurons. In the mature rat, retinal ganglion cells (RGCs) normally fail to regenerate axons through the injured optic nerve but can be stimulated to do so by activating macrophages in the eye (e.g., by lens injury). To investigate underlying changes in gene expression, we retrogradely labeled RGCs with a fluorescent dye, performed optic nerve surgery with or without lens injury, and 4 d later, dissociated retinas, isolated RGCs by fluorescence-activated cell sorting, and examined their profiles of gene expression using microarrays. To investigate the effects of inactivating RhoA, we transfected RGCs with adeno-associated viruses carrying a gene for C3 ribosyltransferase. Our results show that, with appropriate stimulation, mature CNS neurons can undergo dramatic changes in gene expression comparable with those seen in regenerating neurons of the PNS, and that RhoA inactivation by itself results in moderate regeneration, and strongly potentiates axon regeneration through the mature optic nerve when the growth state of neurons is activated.
Key words: retina; optic nerve; axon; regeneration; retinal ganglion cells; gene therapy; microarrays; explants; RhoA
Received April 1, 2004; revised August 26, 2004; accepted August 29, 2004.
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