Multiple promoters direct tissue-specific expression of the rat BDNF gene

Timmusk, Tõnis; Palm, Kaia; Metsis, Madis; Reintam, Tõnu; Paalme, Viiu; Saarma, Märt; Persson, Håkan

doi:10.1016/0896-6273(93)90335-o

Cited by 801 publications

(690 citation statements)

References 61 publications

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“…The cRNA probes and the relative protected fragments (pf) were as follows: BDNF ¼ 800 bp, pf ¼ 740 bp; b-actin (pTRI-b-actin-rat, Ambion) ¼ 164 bp, pf ¼ 126 bp. The cRNA probe of BDNF was complementary to exon V, which is common to all neurotrophin transcripts (Timmusk et al, 1993).…”

Section: Rnase Protection Assaymentioning

confidence: 99%

Chronic Duloxetine Treatment Induces Specific Changes in the Expression of BDNF Transcripts and in the Subcellular Localization of the Neurotrophin Protein

Calabrese

Molteni

Maj

et al. 2007

Neuropsychopharmacol

110

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There is growing evidence that brain-derived neurotrophic factor (BDNF) can be relevant to mood disorders and that modulation of its biosynthesis following prolonged antidepressant treatment may contribute to neuroplastic changes required for clinical response. In the present study, we investigated the effects of the novel antidepressant duloxetine on BDNF in the rat brain. Duloxetine is a serotoninnorepinephrine reuptake inhibitor that differs from other antidepressants by virtue of its balanced potency on both neurotransmitter systems. We found that chronic, but not acute, treatment with duloxetine produces a robust increase of exon V BDNF mRNA levels in frontal cortex when the animals were killed 1 or 24 h after the last administration. The expression of the neurotrophin was also increased in other cortical subregions, but not in the hippocampus. We also found that the increased expression of BDNF in frontal cortex was mainly sustained by enhanced mRNA levels for exons I and III, whereas the expression of exon IV was reduced. Protein analysis in different subcellular fractions showed that chronic treatment with duloxetine, but not with the prototypical SSRI fluoxetine, reduced mature BDNF in the cytosol, but markedly increased its levels in the crude synaptosomal fraction. Our data suggest that chronic treatment with the novel antidepressant duloxetine not only produces a marked upregulation of BDNF mRNA and protein, but may also affect the subcellular redistribution of the neurotrophin. These changes might improve synaptic plasticity and cognitive function that are defective in depressed subjects.

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Section: Rnase Protection Assaymentioning

confidence: 99%

Chronic Duloxetine Treatment Induces Specific Changes in the Expression of BDNF Transcripts and in the Subcellular Localization of the Neurotrophin Protein

Calabrese

Molteni

Maj

et al. 2007

Neuropsychopharmacol

110

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“…Whether SF-1 actively participates in regulating BDNF expression is not known at this time. Elucidating the exact mechanisms governing BDNF expression has proven difficult given that four distinct promoter regions are found in the BDNF upstream genomic sequences (Timmusk et al, 1993;Nakayama et al, 1994) and it is not clear which of the four BDNF transcripts participates in the differentiation of vlVMN neurons. However, we have noted two potential SF-1 binding sites within the 5′ regulatory region of transcript 4 (Liu et al, 2001).…”

Section: Sf-1 and Bdnf In Feeding And Locomotor Behaviorsmentioning

confidence: 99%

Requirement of the orphan nuclear receptor SF-1 in terminal differentiation of ventromedial hypothalamic neurons

Tran

Lee

Marı́n

et al. 2003

Molecular and Cellular Neuroscience

101

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The ventromedial hypothalamic nucleus (VMN) is known to mediate autonomic responses in feeding and reproductive behaviors. To date, the most definitive molecular marker for the VMN is the orphan nuclear receptor steroidogenic factor-1 (SF-1). However, it is unclear whether SF-1 functions in the VMN as it does in peripheral endocrine organ development where loss of SF-1 results in organ agenesis due to apoptosis. Here, we provide evidence that SF-1 has a distinct role in later stages of VMN development by demonstrating the persistence of VMN precursors, the misexpression of an early marker (NKX2-1) concomitant with the absence of a late marker (BDNF neurotrophin), and the complete loss of projections to the bed nucleus of stria terminalis and the amygdala in sf-1 null mice. Our findings demonstrate that SF-1 is required for terminal differentiation of the VMN and suggest that transcriptional targets of SF-1 mediate normal circuitry between the hypothalamus and limbic structures in the telencephalon.

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“…11 The genomic structure of BDNF in rodents is complex, containing multiple 5 0 -untranslated exons and one protein-coding 3 0 exon. [12][13][14] Each of these untranslated exons is alternatively spliced to produce various BDNF mRNA species. Initially, only four untranslated exons were found to be in the rat BDNF gene.…”

Section: Introductionmentioning

confidence: 99%

“…Initially, only four untranslated exons were found to be in the rat BDNF gene. 12 More recent studies show that eight untranslated exons are present in the rodent (mouse and rat) BDNF gene 13,14 and thus these promoters have been renamed. Accordingly, former rat exon III, exon IV and exon V are now termed exon IV, VI and IX, respectively.…”

Section: Introductionmentioning

confidence: 99%

“…14 These rodent BDNF-splicing variants display distinct expression profiles in the brain regions and show differential regulation following treatment of rats with cocaine 13 or kainic acid. 14 Exon IV (formerly rat exon III 12 )-containing transcripts of BDNF are robustly expressed in response to KClinduced membrane depolarization in primary cultures of rat cortical neurons. 15 This transcriptional activation requires the promoter region 80 bp upstream from the transcription initiation site of exon IV-containing three calcium-responsive elements, CaRE1, CaRE2 and CaRE3/CRE, to which their respective stimulating factors, CaRF, USF1/2 and cyclicAMP responsive element binding protein (CREB), are bound.…”

Section: Introductionmentioning

confidence: 99%

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The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons

et al. 2007

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Brain-derived neurotrophic factor (BDNF) has been strongly implicated in the synaptic plasticity, neuronal survival and pathophysiology of depression. Lithium and valproic acid (VPA) are two primary mood-stabilizing drugs used to treat bipolar disorder. Treatment of cultured rat cortical neurons with therapeutic concentrations of LiCl or VPA selectively increased the levels of exon IV (formerly rat exon III)-containing BDNF mRNA, and the activity of BDNF promoter IV. Surprisingly, lithium-or VPA-responsive element(s) in promoter IV resides in a region upstream from the calcium-responsive elements (CaREs) responsible for depolarization-induced BDNF induction. Moreover, activation of BDNF promoter IV by lithium or VPA occurred in cortical neurons depolarized with KCl, and deletion of these three CaREs did not abolish lithium-or VPA-induced activation. Lithium and VPA are direct inhibitors of glycogen synthase kinase-3 (GSK-3) and histone deacetylase (HDAC), respectively. We showed that lithium-induced activation of promoter IV was mimicked by pharmacological inhibition of GSK-3 or short interfering RNA (siRNA)-mediated gene silencing of GSK-3a or GSK-3b isoforms. Furthermore, treatment with other HDAC inhibitors, sodium butyrate and trichostatin A, or transfection with an HDAC1-specific siRNA also activated BDNF promoter IV. Our study demonstrates for the first time that GSK-3 and HDAC are respective initial targets for lithium and VPA to activate BDNF promoter IV, and that this BDNF induction involves a novel responsive region in promoter IV of the BDNF gene. Our results have strong implications for the therapeutic actions of these two mood stabilizers.

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Multiple promoters direct tissue-specific expression of the rat BDNF gene

Cited by 801 publications

References 61 publications

Chronic Duloxetine Treatment Induces Specific Changes in the Expression of BDNF Transcripts and in the Subcellular Localization of the Neurotrophin Protein

Chronic Duloxetine Treatment Induces Specific Changes in the Expression of BDNF Transcripts and in the Subcellular Localization of the Neurotrophin Protein

Requirement of the orphan nuclear receptor SF-1 in terminal differentiation of ventromedial hypothalamic neurons

The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons

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