IDENTIFICATION OF A PUTATIVE ESTROGEN RESPONSE ELEMENT IN THE GENE ENCODING BRAIN-DERIVED NEUROTROPHIC FACTOR

We have been studying the role and mechanism of estrogen action in the survival and differentiation of neurons in the basal forebrain and it s targets in the cerebral cortex, hippocampus, and olfactory bulb. Pre vious work has shown that estrogen-target neurons in these regions wid ely coexpress the mRNAs for the neurotrophin ligands and their recepto rs, suggesting a potential substrate for estrogen-neurotrophin interac tions. Subsequent work indicated that estrogen regulates the expressio n of two neurotrophin receptor mRNAs in prototypic peripheral neural t argets of nerve growth factor. We report herein that the gene encoding the neurotrophin brain-derived neurotrophic factor (BDNF) contains a sequence similar to the canonical estrogen response element found in e strogen-target genes. Gel shift and DNA footprinting assays indicate t hat estrogen receptor-ligand complexes bind to this sequence in the BD NF gene. In vivo, BDNF mRNA was rapidly up-regulated in the cerebral c ortex and the olfactory bulb of ovariectomized animals exposed to estr ogen. These data suggest that estrogen may regulate BDNF transcription , supporting our hypothesis that estrogen may be in a position to infl uence neurotrophin-mediated cell functioning, by increasing the availa bility of specific neurotrophins in forebrain neurons.