On growth and form of the mouse mammary gland
- University of Helsinki, Finland
- INSERM and Sorbonne Universities, UPMC, France
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.
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On growth and form of the mouse mammary glandNCBI Gene Expression Omnibus, GSE225821.
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Fibroblast relays Wnt signals from endothelial niche to mammary epitheliumThe National Omics Data Encyclopedia, China National Center for Bioinformation, OEP001019.
Article and author information
Author details
Mona M Christensen
Martin Holzenberger
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.
Reviewing Editor
- Didier Y Stainier, Max Planck Institute for Heart and Lung Research
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.
Version history
- Preprint posted: April 24, 2023 (view preprint)
- Received: October 5, 2023
- Accepted: March 4, 2024
- Accepted Manuscript published: March 5, 2024 (version 1)
- Version of Record published: March 22, 2024 (version 2)
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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On growth and form of the mouse mammary gland
eLife 13:e93326.
https://doi.org/10.7554/eLife.93326
Further reading
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Amniogenesis, a process critical for continuation of healthy pregnancy, is triggered in a collection of pluripotent epiblast cells as the human embryo implants. Previous studies have established that bone morphogenetic protein (BMP) signaling is a major driver of this lineage specifying process, but the downstream BMP-dependent transcriptional networks that lead to successful amniogenesis remain to be identified. This is, in part, due to the current lack of a robust and reproducible model system that enables mechanistic investigations exclusively into amniogenesis. Here, we developed an improved model of early amnion specification, using a human pluripotent stem cell-based platform in which the activation of BMP signaling is controlled and synchronous. Uniform amniogenesis is seen within 48 hr after BMP activation, and the resulting cells share transcriptomic characteristics with amnion cells of a gastrulating human embryo. Using detailed time-course transcriptomic analyses, we established a previously uncharacterized BMP-dependent amniotic transcriptional cascade, and identified markers that represent five distinct stages of amnion fate specification; the expression of selected markers was validated in early post-implantation macaque embryos. Moreover, a cohort of factors that could potentially control specific stages of amniogenesis was identified, including the transcription factor TFAP2A. Functionally, we determined that, once amniogenesis is triggered by the BMP pathway, TFAP2A controls the progression of amniogenesis. This work presents a temporally resolved transcriptomic resource for several previously uncharacterized amniogenesis states and demonstrates a critical intermediate role for TFAP2A during amnion fate specification.
