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Tissue-specific and neural activity-regulated expression of human BDNF gene in BAC transgenic mice

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is a small secreted protein that has important roles in the developing and adult nervous system. Altered expression or changes in the regulation of the BDNF gene have been implicated in a variety of human nervous system disorders. Although regulat...

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Autores principales: Koppel, Indrek, Aid-Pavlidis, Tamara, Jaanson, Kaur, Sepp, Mari, Pruunsild, Priit, Palm, Kaia, Timmusk, Tõnis
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2708170/
https://www.ncbi.nlm.nih.gov/pubmed/19555478
http://dx.doi.org/10.1186/1471-2202-10-68
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author Koppel, Indrek
Aid-Pavlidis, Tamara
Jaanson, Kaur
Sepp, Mari
Pruunsild, Priit
Palm, Kaia
Timmusk, Tõnis
author_facet Koppel, Indrek
Aid-Pavlidis, Tamara
Jaanson, Kaur
Sepp, Mari
Pruunsild, Priit
Palm, Kaia
Timmusk, Tõnis
author_sort Koppel, Indrek
collection PubMed
description BACKGROUND: Brain-derived neurotrophic factor (BDNF) is a small secreted protein that has important roles in the developing and adult nervous system. Altered expression or changes in the regulation of the BDNF gene have been implicated in a variety of human nervous system disorders. Although regulation of the rodent BDNF gene has been extensively investigated, in vivo studies regarding the human BDNF gene are largely limited to postmortem analysis. Bacterial artificial chromosome (BAC) transgenic mice harboring the human BDNF gene and its regulatory flanking sequences constitute a useful tool for studying human BDNF gene regulation and for identification of therapeutic compounds modulating BDNF expression. RESULTS: In this study we have generated and analyzed BAC transgenic mice carrying 168 kb of the human BDNF locus modified such that BDNF coding sequence was replaced with the sequence of a fusion protein consisting of N-terminal BDNF and the enhanced green fluorescent protein (EGFP). The human BDNF-BAC construct containing all BDNF 5' exons preceded by different promoters recapitulated the expression of endogenous BDNF mRNA in the brain and several non-neural tissues of transgenic mice. All different 5' exon-specific BDNF-EGFP alternative transcripts were expressed from the transgenic human BDNF-BAC construct, resembling the expression of endogenous BDNF. Furthermore, BDNF-EGFP mRNA was induced upon treatment with kainic acid in a promotor-specific manner, similarly to that of the endogenous mouse BDNF mRNA. CONCLUSION: Genomic region covering 67 kb of human BDNF gene, 84 kb of upstream and 17 kb of downstream sequences is sufficient to drive tissue-specific and kainic acid-induced expression of the reporter gene in transgenic mice. The pattern of expression of the transgene is highly similar to BDNF gene expression in mouse and human. This is the first study to show that human BDNF gene is regulated by neural activity.
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spelling pubmed-27081702009-07-09 Tissue-specific and neural activity-regulated expression of human BDNF gene in BAC transgenic mice Koppel, Indrek Aid-Pavlidis, Tamara Jaanson, Kaur Sepp, Mari Pruunsild, Priit Palm, Kaia Timmusk, Tõnis BMC Neurosci Research Article BACKGROUND: Brain-derived neurotrophic factor (BDNF) is a small secreted protein that has important roles in the developing and adult nervous system. Altered expression or changes in the regulation of the BDNF gene have been implicated in a variety of human nervous system disorders. Although regulation of the rodent BDNF gene has been extensively investigated, in vivo studies regarding the human BDNF gene are largely limited to postmortem analysis. Bacterial artificial chromosome (BAC) transgenic mice harboring the human BDNF gene and its regulatory flanking sequences constitute a useful tool for studying human BDNF gene regulation and for identification of therapeutic compounds modulating BDNF expression. RESULTS: In this study we have generated and analyzed BAC transgenic mice carrying 168 kb of the human BDNF locus modified such that BDNF coding sequence was replaced with the sequence of a fusion protein consisting of N-terminal BDNF and the enhanced green fluorescent protein (EGFP). The human BDNF-BAC construct containing all BDNF 5' exons preceded by different promoters recapitulated the expression of endogenous BDNF mRNA in the brain and several non-neural tissues of transgenic mice. All different 5' exon-specific BDNF-EGFP alternative transcripts were expressed from the transgenic human BDNF-BAC construct, resembling the expression of endogenous BDNF. Furthermore, BDNF-EGFP mRNA was induced upon treatment with kainic acid in a promotor-specific manner, similarly to that of the endogenous mouse BDNF mRNA. CONCLUSION: Genomic region covering 67 kb of human BDNF gene, 84 kb of upstream and 17 kb of downstream sequences is sufficient to drive tissue-specific and kainic acid-induced expression of the reporter gene in transgenic mice. The pattern of expression of the transgene is highly similar to BDNF gene expression in mouse and human. This is the first study to show that human BDNF gene is regulated by neural activity. BioMed Central 2009-06-25 /pmc/articles/PMC2708170/ /pubmed/19555478 http://dx.doi.org/10.1186/1471-2202-10-68 Text en Copyright © 2009 Koppel et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Koppel, Indrek
Aid-Pavlidis, Tamara
Jaanson, Kaur
Sepp, Mari
Pruunsild, Priit
Palm, Kaia
Timmusk, Tõnis
Tissue-specific and neural activity-regulated expression of human BDNF gene in BAC transgenic mice
title Tissue-specific and neural activity-regulated expression of human BDNF gene in BAC transgenic mice
title_full Tissue-specific and neural activity-regulated expression of human BDNF gene in BAC transgenic mice
title_fullStr Tissue-specific and neural activity-regulated expression of human BDNF gene in BAC transgenic mice
title_full_unstemmed Tissue-specific and neural activity-regulated expression of human BDNF gene in BAC transgenic mice
title_short Tissue-specific and neural activity-regulated expression of human BDNF gene in BAC transgenic mice
title_sort tissue-specific and neural activity-regulated expression of human bdnf gene in bac transgenic mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2708170/
https://www.ncbi.nlm.nih.gov/pubmed/19555478
http://dx.doi.org/10.1186/1471-2202-10-68
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