Abstract
Brain-derived neurotrophic factor (BDNF) controls the survival, growth, and function of neurons both during the development and in the adult nervous system. Bdnf is transcribed from several distinct promoters generating transcripts with alternative 5' exons. Bdnf transcripts initiated at the first cluster of exons have been associated with the regulation of body weight and various aspects of social behavior, but the mechanisms driving the expression of these transcripts have remained poorly understood. Here, we identify an evolutionarily conserved intronic enhancer region inside the Bdnf gene that regulates both basal and stimulus-dependent expression of the Bdnf transcripts starting from the first cluster of 5' exons in mouse and rat neurons. We further uncover a functional E-box element in the enhancer region, linking the expression of Bdnf and various pro-neural basic helix-loop-helix transcription factors. Collectively, our results shed new light on the cell-type- and stimulus-specific regulation of the important neurotrophic factor BDNF.
Highlights
Brain-derived neurotrophic factor (BDNF) is a secreted protein of the neurotrophin family (Park and Poo, 2013)
To uncover novel enhancer regions regulating Bdnf expression in the central nervous system, we started with bioinformatic analysis of the enhancer-associated characteristics
Our data suggests the role of CREB, AP-1 family proteins, and ATF2 in regulating the neuronal activity-dependent activation of the +3 kb enhancer region, whereas we found no notable evidence of USF family transcription factors and CEBPB regulating the activity of the +3 kb enhancer region
Summary
Brain-derived neurotrophic factor (BDNF) is a secreted protein of the neurotrophin family (Park and Poo, 2013). Rodent Bdnf gene contains eight independently regulated non-coding 5’ exons (exons I–VIII) followed by a single protein-coding 3’ exon (exon IX). Splicing of one of the alternative exons I–VIII with the constitutive exon IX gives rise to different Bdnf transcripts (Aid et al, 2007). The usage of multiple promoters enables complex cell-type- and stimulus-specific Bdnf expression (reviewed in West et al, 2014). Bdnf exon I-, II-, and III-containing transcripts show mainly nervous system-specific expression patterns, whereas Bdnf exon IV- and VI-containing transcripts are expressed in both neural and non-neural tissues (Aid et al, 2007; Timmusk et al, 1993). Similar expression patterns for different BDNF transcripts are observed in humans (Pruunsild et al, 2007). Different Bdnf transcripts have distinct contribution to various aspects of neural
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