Mechanism of life-long maintenance of neuron identity despite molecular fluctuations

  1. Joleen JH Traets
  2. Servaas N van der Burght
  3. Suzanne Rademakers
  4. Gert Jansen
  5. Jeroen S van Zon  Is a corresponding author
  1. AMOLF, Netherlands
  2. University of Cambridge, United Kingdom
  3. Erasmus MC, Netherlands

Abstract

Cell fate is maintained over long timescales, yet molecular fluctuations can lead to spontaneous loss of this differentiated state. Our simulations identified a possible mechanism that explains life-long maintenance of ASE neuron fate in C. elegans by the terminal selector transcription factor CHE-1. Here, fluctuations in CHE-1 level are buffered by the reservoir of CHE-1 bound at its target promoters, which ensures continued che-1 expression by preferentially binding the che-1 promoter. We provide experimental evidence for this mechanism by showing that che-1 expression was resilient to induced transient CHE-1 depletion, while both expression of CHE-1 targets and ASE function were lost. We identified a 130 bp che-1 promoter fragment responsible for this resilience, with deletion of a homeodomain binding site in this fragment causing stochastic loss of ASE identity long after its determination. Because network architectures that support this mechanism are highly conserved in cell differentiation, it may explain stable cell fate maintenance in many systems.

Data availability

All analysed data and analysis scripts are included in the manuscript and supporting files.

Article and author information

Author details

  1. Joleen JH Traets

    Living Matter, AMOLF, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  2. Servaas N van der Burght

    Gurdon Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3272-3815
  3. Suzanne Rademakers

    Department of Cell Biology, Erasmus MC, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  4. Gert Jansen

    Department of Cell Biology, Erasmus MC, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7524-171X
  5. Jeroen S van Zon

    Quantitative Developmental Biology, AMOLF, Amsterdam, Netherlands
    For correspondence
    j.v.zon@amolf.nl
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6021-2924

Funding

Foundation for Fundamental Research on Matter (FOM Vrij Programma)

  • Jeroen S van Zon

Foundation for Fundamental Research on Matter (Fom Vrij Programma)

  • Gert Jansen

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

Reviewing Editor

  1. Silke Hauf, Virginia Tech, United States

Publication history

  1. Preprint posted: April 22, 2020 (view preprint)
  2. Received: January 27, 2021
  3. Accepted: December 14, 2021
  4. Accepted Manuscript published: December 15, 2021 (version 1)
  5. Version of Record published: January 6, 2022 (version 2)

Copyright

© 2021, Traets 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. Joleen JH Traets
  2. Servaas N van der Burght
  3. Suzanne Rademakers
  4. Gert Jansen
  5. Jeroen S van Zon
(2021)
Mechanism of life-long maintenance of neuron identity despite molecular fluctuations
eLife 10:e66955.
https://doi.org/10.7554/eLife.66955
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