Brain-derived neurotrophic factor (BDNF), a member of the nerve growth factor family of neurotrophins, has central roles in the development, physiology, and pathology of the nervous system. We have elucidated the structure of the human BDNF gene, identified alternative transcripts, and studied their expression in adult human tissues and brain regions. In addition, the transcription initiation sites for human BDNF transcripts were determined and the activities of BDNF promoters were analyzed in transient overexpression assays. Our results show that the human BDNF gene has 11 exons and nine functional promoters that are used tissue and brain-region specifically. Furthermore, noncoding natural antisense RNAs that display complex splicing and expression patterns are transcribed in the BDNF gene locus from the antiBDNF gene (approved gene symbol BDNFOS). We show that BDNF and antiBDNF transcripts form dsRNA duplexes in the brain in vivo, suggesting an important role for antiBDNF in regulating BDNF expression in human.

SummaryA global concern has emerged with the pandemic spread of Zika virus (ZIKV) infections that can cause severe neurological symptoms in adults and newborns. ZIKV is a positive-strand RNA virus replicating in virus-induced membranous replication factories (RFs). Here we used various imaging techniques to investigate the ultrastructural details of ZIKV RFs and their relationship with host cell organelles. Analyses of human hepatic cells and neural progenitor cells infected with ZIKV revealed endoplasmic reticulum (ER) membrane invaginations containing pore-like openings toward the cytosol, reminiscent to RFs in Dengue virus-infected cells. Both the MR766 African strain and the H/PF/2013 Asian strain, the latter linked to neurological diseases, induce RFs of similar architecture. Importantly, ZIKV infection causes a drastic reorganization of microtubules and intermediate filaments forming cage-like structures surrounding the viral RF. Consistently, ZIKV replication is suppressed by cytoskeleton-targeting drugs. Thus, ZIKV RFs are tightly linked to rearrangements of the host cell cytoskeleton.

Left-right asymmetrical brain function underlies much of human cognition, behavior and emotion. Abnormalities of cerebral asymmetry are associated with schizophrenia and other neuropsychiatric disorders. The molecular, developmental and evolutionary origins of human brain asymmetry are unknown. We found significant association of a haplotype upstream of the gene LRRTM1 (Leucine-rich repeat transmembrane neuronal 1) with a quantitative measure of human handedness in a set of dyslexic siblings, when the haplotype was inherited paternally (P = 0.00002). While we were unable to find this effect in an epidemiological set of twin-based sibships, we did find that the same haplotype is overtransmitted paternally to individuals with schizophrenia/schizoaffective disorder in a study of 1002 affected families (P = 0.0014). We then found direct confirmatory evidence that LRRTM1 is an imprinted gene in humans that shows a variable pattern of maternal downregulation. We also showed that LRRTM1 is expressed during the development of specific forebrain structures, and thus could influence neuronal differentiation and connectivity. This is the first potential genetic influence on human handedness to be identified, and the first putative genetic effect on variability in human brain asymmetry. LRRTM1 is a candidate gene for involvement in several common neurodevelopmental disorders, and may have played a role in human cognitive and behavioral evolution.

Brain-derived neurotrophic factor (BDNF) is an important mediator of activity-dependent functions of the nervous system and its expression is dysregulated in several neuropsychiatric disorders. Regulation of rodent BDNF neuronal activity-dependent transcription has been relatively well characterized. Here, we have studied regulation of human BDNF (hBDNF) transcription by membrane depolarization of cultured mouse or rat primary cortical neurons expressing hBDNF gene or transfected with hBDNF promoter constructs, respectively. We identified an asymmetric E-box-like element, PasRE [basic helix-loop-helix (bHLH)-PAS transcription factor response element], in hBDNF promoter I and demonstrate that binding of this element by bHLH-PAS transcription factors ARNT2 (aryl hydrocarbon receptor nuclear translocator 2) and NPAS4 (neuronal PAS domain protein 4) is crucial for neuronal activity-dependent transcription from promoter I. We show that binding of CREB (cAMP response element-binding protein) to the cAMP/Ca(2+)-response element (CRE) in hBDNF promoter IV is critical for activity-dependent transcription from this promoter and that upstream stimulatory factor (USF) transcription factors also contribute to the activation by binding to the upstream stimulatory factor binding element (UBE) in hBDNF promoter IV. However, we report that full induction of hBDNF exon IV mRNA transcription is dependent on ARNT2 and NPAS4 binding to a PasRE in promoter IV. Finally, we demonstrate that CRE and PasRE elements in hBDNF promoter IX are required for the induction of this promoter by neuronal activity. Together, the results of this study have identified the cis-elements and transcription factors regulating neuronal activity-dependent transcription of human BDNF gene.

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