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Volume 17, Number 22, Issue of November 15, 1997 pp. 8778-8791

Targeted Overexpression of the Neurite Growth-Associated Protein B-50/GAP-43 in Cerebellar Purkinje Cells Induces Sprouting after Axotomy But Not Axon Regeneration into Growth-Permissive Transplants

Received June 30, 1997; revised Aug. 11, 1997; accepted Aug. 28, 1997.

Annalisa Buffo¹, Anthony J. D. G. Holtmaat², Tiziana Savio⁶, J. Sjef Verbeek³, John Oberdick⁴, A. Beate Oestreicher⁵, Wilhelm Hendrik Gispen⁵, Joost Verhaagen², Ferdinando Rossi¹, and Piergiorgio Strata¹

¹ Department of Neuroscience, University of Turin, I-10125 Turin, Italy, ² Netherlands Institute for Brain Research, 1105 AZ Amsterdam, The Netherlands, ³ Department of Immunology, University of Utrecht, 3584 CG Utrecht, The Netherlands, ⁴ Department of Cell Biology, Neurobiology and Anatomy/Neurobiotechnology Center, The Ohio State University, Columbus, Ohio 43210, ⁵ Rudolf Magnus Institute, University of Utrecht, 3584 CG Utrecht, The Netherlands, and ⁶ Institute of Anatomy, University of Genoa, I-16132 Genoa, Italy

B-50/GAP-43 is a nervous tissue-specific protein, the expression of which is associated with axon growth and regeneration. Its overexpression in transgenic mice produces spontaneous axonal sprouting and enhances induced remodeling in several neuron populations (; ). We examined the capacity of this protein to increase the regenerative potential of injured adult central axons, by inducing targeted B-50/GAP-43 overexpression in Purkinje cells, which normally show poor regenerative capabilities. Thus, transgenic mice were produced in which B-50/GAP-43 overexpression was driven by the Purkinje cell-specific L7 promoter. Uninjured transgenic Purkinje cells displayed normal morphology, indicating that transgene expression does not modify the normal phenotype of these neurons. By contrast, after axotomy numerous transgenic Purkinje cells exhibited profuse sprouting along the axon and at its severed end. Nevertheless, despite these growth phenomena, which never occurred in wild-type mice, the severed transgenic axons were not able to regenerate, either spontaneously or into embryonic neural or Schwann cell grafts placed into the lesion site. Finally, although only a moderate Purkinje cell loss occurred in wild-type cerebella after axotomy, a considerable number of injured transgenic neurons degenerated, but they could be partially rescued by the different transplants placed into the lesion site. Thus, B-50/GAP-43 overexpression substantially modifies Purkinje cell response to axotomy, by inducing growth processes and decreasing their resistance to injury. However, the presence of this protein is not sufficient to enable these neurons to accomplish a full program of axon regeneration.

Key words: transgenic mice; axon growth-associated genes; L7; cerebellum; embryonic neural graft; Schwann cell transplantation

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