RETROGRADE REGULATION OF GROWTH-ASSOCIATED GENE-EXPRESSION IN ADULT-RAT PURKINJE-CELLS BY MYELIN-ASSOCIATED NEURITE GROWTH-INHIBITORY PROTEINS

Axon regeneration requires that injured neurons reinitiate long-distan ce growth and upregulate specific genes. To address the question of wh ether inhibitory environmental cues along the axon could exert a negat ive, tonic downregulation of growth associated genes, we have examined adult rat Purkinje cells, which are endowed with poor regenerative ca pabilities. First we have compared their response to axotomy with that of neurons of the inferior olive, lateral reticular nucleus, and deep cerebellar nuclei. all of which vigorously regenerate into growth-per missive transplants. These injured neurons upregulate the transcriptio n factors c-Jun and JunD, GAP-43, and NADPH diaphorase. In contrast, m ost axotomized Purkinje cells fail to express any of these markers, sh owing that the strength of this response parallels the regenerative po tential of the examined neuron populations. However, strong upregulati on of the same genes can be induced in Purkinje cells after colchicine injection into the uninjured adult cerebellum, indicating that their expression could be controlled by retrograde signals. To assess whethe r myelin-associated neurite growth inhibitory proteins contribute to t his regulation, we applied the neutralizing antibodies IN-1 against on e of the main inhibitory components of central myelin (NI-250) either in vivo or in vitro to organotypic cerebellar cultures. Application of IN-1 antibodies induces the upregulation of c-Jun, JunD, and NADPH di aphorase in Purkinje cells, showing that their expression is suppresse d constitutively by myelin-associated neurite growth inhibitors. Thus, the inhibitory activity of the IN-1 antigen on axon growth is not res tricted to the control of growth cone motility but also involves a ret rograde regulation of gene expression in adult central neurons.