Distinctive four promoters collectively direct expression of brain-derived neurotrophic factor gene.

In order to get a deeper insight into comprehensive understanding of gene regulation of brain-derived neurotrophic factor (BDNF), we characterized the transcriptional apparatus of this gene on the basis of the genomic structure. The results in this study revealed that there are at least four distinctive promoters in the BDNF gene; two of them are neuron-specific and the rest are active in some non-neuronal tissues as well as neuronal ones. Although the analyses of the promoter usage pattern clarified many characteristic features in controlling these promoter activities, the most notable finding was that administration of kainic acid resulted in great activation of two out of the four promoters in hippocampal neurons in a regionally different manner and thus indicated the presence of two distinct signal transduction pathways for kainate-induced activation of BDNF gene expression in neurons. The analysis of BDNF gene expression in terms of the promoter usage pattern would provide a new and important insight into understanding a molecular control mechanism of this gene expression.

[1]  J. Auwerx,et al.  Activation of junB by PKC and PKA signal transduction through a novel cis-acting element. , 1991, Nucleic acids research.

[2]  D. Ghosh,et al.  A relational database of transcription factors. , 1990, Nucleic acids research.

[3]  H. Thoenen,et al.  Activity dependent regulation of BDNF and NGF mRNAs in the rat hippocampus is mediated by non‐NMDA glutamate receptors. , 1990, The EMBO journal.

[4]  David J. Anderson,et al.  A cell type-preferred silencer element that controls the neural-specific expression of the SCG10 gene , 1990, Neuron.

[5]  H. Thoenen,et al.  Molecular cloning and expression of brain-derived neurotrophic factor , 1989, Nature.

[6]  E. Castrén,et al.  Regulation of brain-derived neurotrophic factor and nerve growth factor mRNA in primary cultures of hippocampal neurons and astrocytes , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[7]  O. Osamu,et al.  A rat brain-derived neurotrophic factor-encoding gene generates multiple transcripts through alternative use of 5′exons and polyadenylation sites , 1992 .

[8]  M. Saarma,et al.  Multiple promoters direct tissue-specific expression of the rat BDNF gene , 1993, Neuron.

[9]  D. Nathans,et al.  DNA binding site of the growth factor-inducible protein Zif268. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[10]  M. Chao,et al.  A constitutive promoter directs expression of the nerve growth factor receptor gene. , 1988, Molecular and cellular biology.

[11]  L. Belluscio,et al.  Neurotrophin-3: a neurotrophic factor related to NGF and BDNF. , 1990, Science.

[12]  H. Thoenen,et al.  Enhanced synthesis of brain-derived neurotrophic factor in the lesioned peripheral nerve: different mechanisms are responsible for the regulation of BDNF and NGF mRNA , 1992, The Journal of cell biology.

[13]  A. Sauerwald,et al.  The 5'-flanking region of the synapsin I gene. A G+C-rich, TATA- and CAAT-less, phylogenetically conserved sequence with cell type-specific promoter function. , 1990, The Journal of biological chemistry.

[14]  Steven A. Johnson,et al.  BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer's disease , 1991, Neuron.

[15]  H. Tojo,et al.  cDNA cloning and sequence determination of rat membrane-associated phospholipase A2. , 1989, Biochemical and biophysical research communications.

[16]  M. A. Thompson,et al.  Structure of the gene encoding Peripherin, an NGF-regulated neuronal-specific type III intermediate filament protein , 1989, Neuron.

[17]  L. Belluscio,et al.  NT-3, BDNF, and NGF in the developing rat nervous system: Parallel as well as reciprocal patterns of expression , 1990, Neuron.

[18]  Richard F. Thompson,et al.  BDNF mRNA expression in the developing rat brain following kainic acid-induced seizure activity , 1992, Neuron.

[19]  P. Schwartzkroin,et al.  Neurotrophin expression in rat hippocampal slices: A stimulus paradigm inducing LTP in CA1 evokes increases in BDNF and NT-3 mRNAs , 1992, Neuron.

[20]  S. Snyder.  Fresh factors to consider , 1991, Nature.

[21]  Y. Barde,et al.  Regional distribution of brain‐derived neurotrophic factor mRNA in the adult mouse brain. , 1990, The EMBO journal.

[22]  E. Nedivi,et al.  A neural-specific GAP-43 core promoter located between unusual DNA elements that interact to regulate its activity , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[23]  Y. Ono,et al.  Characterization of the 5'-flanking region of the human brain-derived neurotrophic factor gene. , 1992, Biochemical and biophysical research communications.

[24]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[25]  S M de la Monte,et al.  Human and rat brain-derived neurotrophic factor and neurotrophin-3: gene structures, distributions, and chromosomal localizations. , 1991, Genomics.

[26]  S. Oka,et al.  Inflammatory factors stimulate expression of group II phospholipase A2 in rat cultured astrocytes. Two distinct pathways of the gene expression. , 1991, The Journal of biological chemistry.

[27]  S. Lewis,et al.  Anomalous placement of introns in a member of the intermediate filament multigene family: an evolutionary conundrum , 1986, Molecular and cellular biology.