Abstract

The mammary gland is a unique organ that undergoes dynamic alterations throughout a female's reproductive life, making it an ideal model for developmental, stem cell and cancer biology research. Mammary gland development begins in utero and proceeds via a quiescent bud stage before the initial outgrowth and subsequent branching morphogenesis. How mammary epithelial cells transit from quiescence to an actively proliferating and branching tissue during embryogenesis and, importantly, how the branch pattern is determined remain largely unknown. Here we provide evidence indicating that epithelial cell proliferation and onset of branching are independent processes, yet partially coordinated by the Eda signaling pathway. Through heterotypic and heterochronic epithelial-mesenchymal recombination experiments between mouse mammary and salivary gland tissues and ex vivo live imaging, we demonstrate that unlike previously concluded, the mode of branching is an intrinsic property of the mammary epithelium whereas the pace of growth and the density of ductal tree are determined by the mesenchyme. Transcriptomic profiling and ex vivo and in vivo functional studies in mice disclose that mesenchymal Wnt/ß-catenin signaling, and in particular IGF-1 downstream of it critically regulate mammary gland growth. These results underscore the general need to carefully deconstruct the different developmental processes producing branched organs.

Data availability

Sequencing data have been deposited in GEO under accession code GSE225821.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Qiang Lan

    Institute of Biotechnology, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7765-6767
  2. Ewelina Trela

    Institute of Biotechnology, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
  3. Riitta Lindström

    Institute of Biotechnology, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5177-0564
  4. Jyoti Prabha Satta

    Institute of Biotechnology, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
  5. Beata Kaczyńska

    Institute of Biotechnology, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
  6. Mona M Christensen

    Institute of Biotechnology, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0655-8665
  7. Martin Holzenberger

    Research Center UMRS938, INSERM and Sorbonne Universities, UPMC, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4869-725X
  8. Jukka Jernvall

    Institute of Biotechnology, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6575-8486
  9. Marja L Mikkola

    Institute of Biotechnology, University of Helsinki, Helsinki, Finland
    For correspondence
    marja.mikkola@helsinki.fi
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9890-3835

Funding

Research Council of Finland (318287)

  • Marja L Mikkola

Sigrid Juséliuksen Säätiö

  • Marja L Mikkola

Helsinki Institute of Life Science, Helsingin Yliopisto

  • Marja L Mikkola

Helsingin Yliopiston Tiedesäätiö

  • Ewelina Trela

Helsingin Yliopiston Tiedesäätiö

  • Mona M Christensen

Suomen Kulttuurirahasto

  • Jyoti Prabha Satta

Ella ja Georg Ehrnroothin Säätiö

  • Jyoti Prabha Satta

Oskar Öflunds Stiftelse

  • Qiang Lan

Suomen Kulttuurirahasto

  • Beata Kaczyńska

Research Council of Finland (272280)

  • Marja L Mikkola

Research Council of Finland (307421)

  • Marja L Mikkola

Cancer Society of Finland

  • Marja L Mikkola

Jane ja Aatos Erkon Säätiö

  • Marja L Mikkola

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 mouse experiments were approved by the Laboratory Animal Center at the University of Helsinki and the National Animal Experiment Board of Finland with the licenses number KEK19-019, KEK22-014 and ESAVI/2363/04.10.07/2017. Mice were euthanized with CO2 followed by cervical dislocation.

Copyright

© 2024, Lan 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. Qiang Lan
  2. Ewelina Trela
  3. Riitta Lindström
  4. Jyoti Prabha Satta
  5. Beata Kaczyńska
  6. Mona M Christensen
  7. Martin Holzenberger
  8. Jukka Jernvall
  9. Marja L Mikkola
(2024)
On growth and form of the mouse mammary gland
eLife 13:e93326.
https://doi.org/10.7554/eLife.93326

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https://doi.org/10.7554/eLife.93326