Expression of Specific Tubulin Isotypes Increases during Regeneration of Injured CNS Neurons, But Not after the Application of Brain-Derived Neurotrophic Factor (BDNF)

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Abstract
Axonal regrowth after injury is accompanied by changes in the expression of tubulin, but the contributions of substrate molecules and neurotrophic factors in regulating these changesin vivoare not known. Adult rat retinal ganglion cells (RGCs) were examined after intraorbital axotomy, after application of a peripheral nerve (PN) graft to stimulate regeneration, and after axotomy and treatment with brain-derived neurotrophic factor (BDNF). After these treatments we usedin situhybridization to study mRNA levels for βI, βII, βIII, βIVa, and Tα1 tubulin isotypes. Levels of mRNA for all isotypes were downregulated after intraorbital axotomy. During regrowth of injured RGC axons, mRNA levels for βII, βIII, and Tα1 isotypes were upregulated specifically and dramatically, suggesting that elevated expression of these isotypes is correlated specifically with axonal regrowth. A corresponding increase in βIII protein levels was detected by immunocytochemistry. The βI and βIVamRNAs were not increased during regeneration. BDNF did not elicit a specific increase in the mRNA levels for the βIII and Tα1 isotypes and had only a small effect on mRNA levels for the βII isotype. Therefore, despite the ability of BDNF to support the survival of injured RGCs and to enhance neurite outgrowth of retinal neuronsin vitro, thein vivoapplication of BDNF alone is unable to induce the program of changes in growth-associated tubulins that accompany regeneration of RGC axons into PN grafts. We speculate that, in addition to BDNF, cooperative signaling with substrate molecules is required to allow RGCs to regenerate and exhibit tubulin isotype switching.