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Abstract

Transcription of the brain-derived neurotrophic factor (BDNF) gene is regulated in a calcium- and neuron-selective manner; however, the mechanisms that underlie this selectivity are not known. We have characterized a new calcium-response element, CaRE1, that is required for activity-dependent transcription of BDNF exon III and have cloned a transcription factor, CaRF, that activates transcription from BDNF promoter III in a CaRE1-dependent manner. The transcriptional activity of CaRF is regulated in a calcium- and neuron-selective manner, suggesting that CaRF may confer selectivity upon the activity-dependent induction of BDNF exon III expression.

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Calcium regulation of neuronal gene expression.

A E West, W. G. Chen, M Dalva … (2001)

Plasticity is a remarkable feature of the brain, allowing neuronal structure and function to accommodate to patterns of electrical activity. One component of these long-term changes is the activity-driven induction of new gene expression, which is required for both the long-lasting long-term potentiation of synaptic transmission associated with learning and memory, and the activity dependent survival events that help to shape and wire the brain during development. We have characterized molecular mechanisms by which neuronal membrane depolarization and subsequent calcium influx into the cytoplasm lead to the induction of new gene transcription. We have identified three points within this cascade of events where the specificity of genes induced by different types of stimuli can be regulated. By using the induction of the gene that encodes brain-derived neurotrophic factor (BDNF) as a model, we have found that the ability of a calcium influx to induce transcription of this gene is regulated by the route of calcium entry into the cell, by the pattern of phosphorylation induced on the transcription factor cAMP-response element (CRE) binding protein (CREB), and by the complement of active transcription factors recruited to the BDNF promoter. These results refine and expand the working model of activity-induced gene induction in the brain, and help to explain how different types of neuronal stimuli can activate distinct transcriptional responses.

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CREB: a Ca(2+)-regulated transcription factor phosphorylated by calmodulin-dependent kinases.

E. Peter Greenberg, Z. M. Sheng, Gloria M A Thompson (1991)

The mechanism by which Ca2+ mediates gene induction in response to membrane depolarization was investigated. The adenosine 3',5'-monophosphate (cAMP) response element-binding protein (CREB) was shown to function as a Ca(2+)-regulated transcription factor and as a substrate for depolarization-activated Ca(2+)-calmodulin-dependent protein kinases (CaM kinases) I and II. CREB residue Ser133 was the major site of phosphorylation by the CaM kinases in vitro and of phosphorylation after membrane depolarization in vivo. Mutation of Ser133 impaired the ability of CREB to respond to Ca2+. These results suggest that CaM kinases may transduce electrical signals to the nucleus and that CREB functions to integrate Ca2+ and cAMP signals.

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Molecular cloning and expression of brain-derived neurotrophic factor.

M Hofer, H Thoenen, Y Barde … (1989)

During the development of the vertebrate nervous system, many neurons depend for survival on interactions with their target cells. Specific proteins are thought to be released by the target cells and to play an essential role in these interactions. So far, only one such protein, nerve growth factor, has been fully characterized. This has been possible because of the extraordinarily (and unexplained) large quantities of this protein in some adult tissues that are of no relevance to the developing nervous system. Whereas the dependency of many neurons on their target cells for normal development, and the restricted neuronal specificity of nerve growth factor have long suggested the existence of other such proteins, their low abundance has rendered their characterization difficult. Here we report the full primary structure of brain-derived neurotrophic factor. This very rare protein is known to promote the survival of neuronal populations that are all located either in the central nervous system or directly connected with it. The messenger RNA for brain-derived neurotrophic factor was found predominantly in the central nervous system, and the sequence of the protein indicates that it is structurally related to nerve growth factor. These results establish that these two neurotrophic factors are related both functionally and structurally.

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PubMed ID:: 11832226

DOI:: 10.1016/S0896-6273(01)00561-X

ScienceOpen disciplines: Chemistry

Keywords: 1-Methyl-3-isobutylxanthine,pharmacology,Amino Acid Sequence,Animals,Brain,cytology,metabolism,Brain-Derived Neurotrophic Factor,genetics,Calcium,Cells, Cultured,Cyclic AMP,analogs & derivatives,Exons,Gene Expression Regulation,physiology,Genes, Reporter,Humans,In Situ Hybridization,Microscopy, Fluorescence,Molecular Sequence Data,Neurons,drug effects,Nuclear Proteins,Phosphodiesterase Inhibitors,Rats,Rats, Long-Evans,Regulatory Sequences, Nucleic Acid,Response Elements,Tissue Distribution,Transcription Factors,chemistry,Two-Hybrid System Techniques

A calcium-responsive transcription factor, CaRF, that regulates neuronal activity-dependent expression of BDNF.

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Most cited references 26

Calcium regulation of neuronal gene expression.

CREB: a Ca(2+)-regulated transcription factor phosphorylated by calmodulin-dependent kinases.

Molecular cloning and expression of brain-derived neurotrophic factor.

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