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

  1. Jürgen Tuvikene  Is a corresponding author
  2. Eli-Eelika Esvald
  3. Annika Rähni
  4. Kaie Uustalu
  5. Anna Zhuravskaya
  6. Annela Avarlaid
  7. Eugene V Makeyev
  8. Tõnis Timmusk  Is a corresponding author
  1. Tallinn University of Technology, Estonia
  2. Kings College London, United Kingdom

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

Article and author information

Author details

  1. 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.
  2. Eli-Eelika Esvald

    Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia
    Competing interests
    The authors declare that no competing interests exist.
  3. Annika Rähni

    Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2826-4636
  4. Kaie Uustalu

    Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia
    Competing interests
    The authors declare that no competing interests exist.
  5. Anna Zhuravskaya

    MRC Centre for Developmental Neurobiology, Kings College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Annela Avarlaid

    Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia
    Competing interests
    The authors declare that no competing interests exist.
  7. Eugene V Makeyev

    MRC Centre for Developmental Neurobiology, Kings College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. 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.
    ORCID icon "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.

Reviewing Editor

  1. Anne E West, Duke University School of Medicine, United States

Publication history

  1. Received: November 25, 2020
  2. Accepted: February 8, 2021
  3. Accepted Manuscript published: February 9, 2021 (version 1)
  4. Version of Record published: February 18, 2021 (version 2)

Copyright

© 2021, Tuvikene et al.

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.

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  1. Jürgen Tuvikene
  2. Eli-Eelika Esvald
  3. Annika Rähni
  4. Kaie Uustalu
  5. Anna Zhuravskaya
  6. Annela Avarlaid
  7. Eugene V Makeyev
  8. Tõnis Timmusk
(2021)
Intronic enhancer region governs transcript-specific Bdnf expression in rodent neurons
eLife 10:e65161.
https://doi.org/10.7554/eLife.65161

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