The brain-derived neurotrophic factor (BDNF) is essential for the survival of neurons in the central nervous system (CNS). The expression of BDNF is regulated by several conditions related to neuronal activity including seizures, normal neuronal depolarization, and long-term potentiation (LTP)--all mechanisms that increase intracellular concentrations of calcium. Increased calcium leads to the occupation of calcium-adenosine-3′,5′-monophosphate (cAMP) response element (CRE) in the BDNF promoter by transcription factors of the CRE-binding protein (CREB) family. The BDNF gene contains four noncoding exons located 5′ to the coding region, each of which can be alternatively spliced to the 3′ coding exon. BDNF mRNAs that contain the nontranslated exon 3 are the most highly expressed isoform in response to membrane depolarization. In an attempt to understand the processes that contribute to activity-induced neuronal gene-expression, Tao et al. have identified a new mechanism by which BDNF expression is increased. The expression of BDNF genes that contained CRE mutations was still enhanced in response to increases in calcium concentrations, suggesting that another promoter element was responsible for regulating exon 3-containing BDNF expression. The authors identified a new calcium-response element (CaRE1), and used a yeast one-hybrid assay to clone and characterize a transcription factor (calcium-responsive transcription factor, CaRF) that specifically bound to CaRE1. Expression of exon 3-containing BDNF transcripts could be increased through calcium-regulated mechanisms, in the absence of increased cAMP concentrations, which suggests that CaRE1 and CaRF could promote transcription of BDNF in the absence of CREB activity. Thus, the data indicate that CaRF might function in calcium-mediated neuronal development and plasticity.
X. Tao, A. E. West, W. G. Chen, G. Corfas, M. E. Greenberg, A calcium-responsive transcription factor, CaRF, that regulates neuronal activity-dependent expression of CaRF. Neuron 33, 383-395 (2002). [Online Journal]