Dissecting the human BDNF locus: Bidirectional transcription, complex splicing, and multiple promoters

Pruunsild, Priit; Kazantseva, Anna; Aid, Tamara; Palm, Kaia; Timmusk, Tõnis

doi:10.1016/j.ygeno.2007.05.004

Cited by 621 publications

(584 citation statements)

References 40 publications

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“…These promoters were targeted because they generate the majority of BDNF in the brain Pruunsild et al, 2007). Targeting was accomplished by genetically engineering the placement of an eGFP-STOP cassette upstream of the respective 5′-UTR splice donor site of the targeted exon (Supplementary Figure S1a) with a floxed PGK-Neo cassette inserted antisense to eGFP-STOP for selection.…”

Section: Disruption Of Bdnf Production From Specific Promotersmentioning

confidence: 99%

“…To determine the biological significance of this 'multiple promoter, same protein' mechanism, we generated four transgenic mouse lines in which BDNF production is selectively disrupted from one of the four major promoters I, II, IV, or VI (Bdnf-e1, -e2, -e4, and -e6 mice). We targeted transcripts containing 5′-untranslated region (5′-UTR) exons I, II, IV, and VI, because they constitute the majority of BDNF mRNAs produced in the brain Pruunsild et al, 2007). As BDNF production is only impaired from a single promoter, these models allow us to assess how loss of BDNF from one promoter vs another results in different consequences at the molecular, cellular, and behavioral levels.…”

Section: Introductionmentioning

confidence: 99%

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Functional Role of BDNF Production from Unique Promoters in Aggression and Serotonin Signaling

Maynard

Hill

Calcaterra

et al. 2015

Neuropsychopharmacol

101

150

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Brain-derived neurotrophic factor (BDNF) regulates diverse biological functions ranging from neuronal survival and differentiation during development to synaptic plasticity and cognitive behavior in the adult. BDNF disruption in both rodents and humans is associated with neurobehavioral alterations and psychiatric disorders. A unique feature of Bdnf transcription is regulation by nine individual promoters, which drive expression of variants that encode an identical protein. It is hypothesized that this unique genomic structure may provide flexibility that allows different factors to regulate BDNF signaling in distinct cell types and circuits. This has led to the suggestion that isoforms may regulate specific BDNF-dependent functions; however, little scientific support for this idea exists. We generated four novel mutant mouse lines in which BDNF production from one of the four major promoters (I, II, IV, or VI) is selectively disrupted (Bdnf-e1, -e2, -e4, and -e6 mice) and used a comprehensive comparator approach to determine whether different Bdnf transcripts are associated with specific BDNF-dependent molecular, cellular, and behavioral phenotypes. Bdnf-e1 and -e2 mutant males displayed heightened aggression accompanied by convergent expression changes in specific genes associated with serotonin signaling. In contrast, BDNF-e4 and -e6 mutants were not aggressive but displayed impairments associated with GABAergic gene expression. Moreover, quantifications of BDNF protein in the hypothalamus, prefrontal cortex, and hippocampus revealed that individual Bdnf transcripts make differential, regionspecific contributions to total BDNF levels. The results highlight the biological significance of alternative Bdnf transcripts and provide evidence that individual isoforms serve distinct molecular and behavioral functions.

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Section: Disruption Of Bdnf Production From Specific Promotersmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Functional Role of BDNF Production from Unique Promoters in Aggression and Serotonin Signaling

Maynard

Hill

Calcaterra

et al. 2015

Neuropsychopharmacol

101

150

View full text Add to dashboard Cite

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“…Multiple BDNF transcripts are generated by alternative splicing of one 5Ј exon with a shared 3Ј exon containing the entire BDNF coding region and either a short or long 3Ј UTR sequence (5,6). In recent studies, we have demonstrated that BDNF transcripts differ in their subcellular localization (7).…”

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confidence: 99%

Dendritic trafficking of BDNF mRNA is mediated by translin and blocked by the G196A (Val66Met) mutation

Chiaruttini

Vicario

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

202

229

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Alternatively spliced brain-derived neurotrophic factor (BDNF) transcripts are targeted to distinct cellular compartments in neurons but the mechanisms underlying this sorting are unknown. Although only some BDNF isoforms are targeted to dendrites, we have found that the coding region common to all BDNF transcripts contains a constitutively active dendritic targeting signal and that this signal is suppressed in transcripts containing exons 1 or 4, which are restricted to the cell soma and proximal dendrites. This dendritic targeting signal is mediated by translin, an RNA-binding protein implicated in RNA trafficking, and is disrupted by the G196A mutation associated with memory deficits and psychiatric disorders. Molecular modeling and mutational studies indicate that the G196A mutation blocks dendritic targeting of BDNF mRNA by disrupting its interaction with translin. These findings implicate abnormal dendritic trafficking of BDNF mRNA in the pathophysiology of neuropsychiatric disorders linked to the G196A mutation.neuropsychiatric disorders ͉ neurotrophins S everal lines of evidence indicate that targeting of BDNF mRNA to dendrites plays a key role in mediating synaptic plasticity (1-4). However, the molecular mechanisms regulating this process and the differential subcellular localization of alternatively spliced BDNF transcripts, remain to be clarified.Multiple BDNF transcripts are generated by alternative splicing of one 5Ј exon with a shared 3Ј exon containing the entire BDNF coding region and either a short or long 3Ј UTR sequence (5, 6). In recent studies, we have demonstrated that BDNF transcripts differ in their subcellular localization (7). Exon 1 and 4 transcripts are localized in the cell soma, while exon 2 and 6 transcripts show a somato-dendritic localization. Thus, splice variants appear to encode spatial localization signals used to preferentially regulate BDNF expression in different subcellular domains (2, 3). A recent study has suggested that the long 3Ј UTR contains signals necessary for dendritic targeting of BDNF transcripts (4). However, it is unlikely that this mechanism can fully account for the differential dendritic targeting displayed by BDNF transcripts because more than one-third of exon 4 transcripts, which are retained in the soma, contain the long 3Ј UTR. Conversely, more than one-half of exon 6 transcripts, an isoform that displays targeting to dendrites, contain the short 3Ј UTR. To help define the mechanisms underlying differential localization of BDNF transcripts, we have tested the hypothesis that additional signals might be encoded by other BDNF mRNA regions.

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“…3 Of these variants, BDNF-IV is the most commonly studied and its expression changes have been associated with behavioural phenotypes, psychiatric disorders and epigenetic modifications. 4 The promoter region in exon-IV contains specific binding sites for the cyclic-AMP-responsive-elementbinding protein (CREB) 5 and the methyl-CpG-binding-protein-2 (MeCP2) 6 making it a preferential candidate for epigenetic regulation.…”

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confidence: 99%

Epigenetic regulation of BDNF expression according to antidepressant response

et al. 2012

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Several lines of evidence support the role of Brain-Derived Neurotrophic Factor (BDNF) in the pathophysiology and pharmacotherapy of depression. 1 The neurotrophin hypothesis of depression postulates that stress and depression are associated with decreased BDNF expression that can be reversed by antidepressant treatment. 2 The goal of the present study was to investigate the effect of antidepressant treatment on the epigenetic regulation of BDNF in major depressive disorder (MDD).The BDNF gene has distinct splice variants, each one regulated by a specific promoter region, that determine tissue-specific regulation of expression. 3 Of these variants, BDNF-IV is the most commonly studied and its expression changes have been associated with behavioural phenotypes, psychiatric disorders and epigenetic modifications. 4 The promoter region in exon-IV contains specific binding sites for the cyclic-AMP-responsive-elementbinding protein (CREB) 5 and the methyl-CpG-binding-protein-2 (MeCP2) 6 making it a preferential candidate for epigenetic regulation.Tsankova et al. 7 reported that mice exposed to chronic social defeat stress displayed lower levels of BDNF-IV associated with a significant increase in histone H3 lysine 27 trimethylation (H3K27me3), a modification associated with transcriptional repression. Long term imipramine treatment reversed BDNF-IV down-regulation to baseline levels. 7 Studies by our group in postmortem brain of depressed subjects with or without history of antidepressant treatment compared to controls, showed an increased expression of BDNF-IV and a decrease of H3K27 tri-methylation levels in subjects treated with antidepressants only. 8In order to investigate the epigenetic regulation of BDNF in MDD patients according to antidepressant treatment, we conducted a prospective study in 25 treatment-naïve MDD patients. All patients had Hamilton Rating Scale for Depression [HAM-D] scores equal or above 24 at baseline (N=25, X=29.4 ± 1.2). All participants gave written informed consent for this study, approved by our Institutional Review Board.

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Dissecting the human BDNF locus: Bidirectional transcription, complex splicing, and multiple promoters

Cited by 621 publications

References 40 publications

Functional Role of BDNF Production from Unique Promoters in Aggression and Serotonin Signaling

Functional Role of BDNF Production from Unique Promoters in Aggression and Serotonin Signaling

Dendritic trafficking of BDNF mRNA is mediated by translin and blocked by the G196A (Val66Met) mutation

Epigenetic regulation of BDNF expression according to antidepressant response

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