Intronic enhancer region governs transcript-specific Bdnf expression in rodent neurons

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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.

Data availability

Mass-spectrometry results of the in vitro DNA pulldown experiment are provided in Supplementary Table 3.

The following previously published data sets were used

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Article and author information

Author details

Jürgen Tuvikene

Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia

For correspondence
jurgen.tuvikene@taltech.ee

Competing interests
The authors declare that no competing interests exist.
Eli-Eelika Esvald

Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia

Competing interests
The authors declare that no competing interests exist.
Annika Rähni

Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-2826-4636
Kaie Uustalu

Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia

Competing interests
The authors declare that no competing interests exist.
Anna Zhuravskaya

MRC Centre for Developmental Neurobiology, Kings College London, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Annela Avarlaid

Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia

Competing interests
The authors declare that no competing interests exist.
Eugene V Makeyev

MRC Centre for Developmental Neurobiology, Kings College London, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Tõnis Timmusk

Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia

For correspondence
tonis.timmusk@taltech.ee

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1015-3348

Funding

Estonian Research Council (IUT19-18)

Jürgen Tuvikene
Eli-Eelika Esvald
Annika Rähni
Kaie Uustalu
Annela Avarlaid
Tõnis Timmusk

Estonian Research Council (PRG805)

Jürgen Tuvikene
Eli-Eelika Esvald
Annela Avarlaid
Tõnis Timmusk

Norwegian Financial Mechanism (EMP128)

Jürgen Tuvikene
Eli-Eelika Esvald
Annika Rähni
Kaie Uustalu
Tõnis Timmusk

European Regional Development Fund (2014-2020.4.01.15-0012)

Jürgen Tuvikene
Eli-Eelika Esvald
Annika Rähni
Kaie Uustalu
Annela Avarlaid
Tõnis Timmusk

H2020-MSCA-RISE-2016 (EU734791)

Jürgen Tuvikene
Eli-Eelika Esvald
Anna Zhuravskaya
Annela Avarlaid
Eugene V Makeyev
Tõnis Timmusk

Biotechnology and Biological Sciences Research Council (BB/M001199/1)

Anna Zhuravskaya
Eugene V Makeyev

Biotechnology and Biological Sciences Research Council (BB/M007103/1)

Anna Zhuravskaya
Eugene V Makeyev

Biotechnology and Biological Sciences Research Council (BB/R001049/1)

Anna Zhuravskaya
Eugene V Makeyev

European Regional Development Fund (ASTRA 2014-2020.4.01.16-0032)

Jürgen Tuvikene
Eli-Eelika Esvald
Annela Avarlaid
Tõnis Timmusk

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.