IDENTIFICATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR PROMOTER REGIONS MEDIATING TISSUE-SPECIFIC, AXOTOMY-INDUCED, AND NEURONAL ACTIVITY-INDUCED EXPRESSION IN TRANSGENIC MICE

The structure of rat brain-derived neurotrophic factor (BDNF) gene is complex; four 5' exons are linked to separate promoters and one 3' exo n is encoding the BDNF protein. To analyze the relative importance of the regulatory regions in vivo, we have generated transgenic mice with six different promoter constructs of the BDNF gene fused to the chlor amphenicol acetyl transferase reporter gene. High level and neuronal e xpression of the reporter gene, that in many respects recapitulated BD NF gene expression, was achieved by using 9 kb of genomic sequences co vering the promoter regions that lie adjacent to each other in the gen ome (promoters I and II and promoters III and IV, respectively) and by including sequences of BDNF intron-exon splice junctions and 3' untra nslated region in the constructs. The genomic regions responsible for the in vivo upregulation of BDNF expression in the axotomized sciatic nerve and in the brain after kainic acid-induced seizures and KCl-indu ced spreading depression were mapped. These data show that regulation of the different aspects of BDNF expression is controlled by different regions in vivo, and they suggest that these promoter constructs may be useful for targeted expression of heterologous genes to specific re gions of the central and peripheral nervous systems in an inducible ma nner.