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SOX21 modulates SOX2-initiated differentiation of epithelial cells in the extrapulmonary airways

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Cite this article as: eLife 2021;10:e57325 doi: 10.7554/eLife.57325

Abstract

SOX2 expression levels are crucial for the balance between maintenance and differentiation of airway progenitor cells during development and regeneration. Here, we describe patterning of the mouse proximal airway epithelium by SOX21, which coincides with high levels of SOX2 during development. Airway progenitor cells in this SOX2+/SOX21+ zone show differentiation to basal cells, specifying cells for the extrapulmonary airways. Loss of SOX21 showed an increased differentiation of SOX2+ progenitor cells to basal and ciliated cells during mouse lung development. We propose a mechanism where SOX21 inhibits differentiation of airway progenitors by antagonizing SOX2-induced expression of specific genes involved in airway differentiation. Additionally, in the adult tracheal epithelium SOX21 inhibits basal to ciliated cell differentiation. This suppressing function of SOX21 on differentiation contrasts SOX2, which mainly drives differentiation of epithelial cells during development and regeneration after injury. Furthermore, using human fetal lung organoids and adult bronchial epithelial cells, we show that SOX2+/SOX21+ regionalization is conserved. Lastly, we show that the interplay between SOX2 and SOX21 is context and concentration dependent leading to regulation of differentiation of the airway epithelium.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1 to 6

Article and author information

Author details

  1. Evelien Eenjes

    Pediatric Surgery, Erasmus University Medical Center, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  2. Marjon Buscop-van Kempen

    Pediatric Surgery, Erasmus University Medical Center, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  3. Anne Boerema-de Munck

    Pediatric Surgery, Erasmus University Medical Center, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  4. Gabriela G Edel

    Pediatric Surgery, Erasmus University Medical Center, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  5. Floor Benthem

    Pediatric Surgery, Erasmus University Medical Center, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  6. Lisette de Kreij-de Bruin

    Pediatric Surgery, Erasmus University Medical Center, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  7. Marco Schnater

    Pediatric Surgery, Erasmus University Medical Center, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  8. Dick Tibboel

    Pediatric Surgery, Erasmus University Medical Center, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  9. Jennifer Collins

    Pediatric Surgery, Erasmus University Medical Center, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  10. Robbert J Rottier

    Pediatric Surgery/Cell Biology, Erasmus University Medical Center, Rotterdam, Netherlands
    For correspondence
    r.rottier@erasmusmc.nl
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9291-4971

Funding

Sophia Foundation for Medical Research (S14-12)

  • Evelien Eenjes

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

Ethics

Animal experimentation: All animal experimental protocols were approved the national committee ("Centrale Commissie Dierproeven"; number AVD101002017871) and by the animal welfare committee of the veterinary authorities (prtocol numbers 17-871-01 and 17-871-02) of the Erasmus Medical Center.

Reviewing Editor

  1. Melanie Königshoff, University of Pittsburgh, United States

Publication history

  1. Received: March 27, 2020
  2. Accepted: July 20, 2021
  3. Accepted Manuscript published: July 21, 2021 (version 1)

Copyright

© 2021, Eenjes 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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