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.
-
On growth and form of the mouse mammary glandNCBI Gene Expression Omnibus, GSE225821.
-
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.
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.
Metrics
-
- 839
- views
-
- 160
- downloads
-
- 3
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
On growth and form of the mouse mammary gland
eLife 13:e93326.
https://doi.org/10.7554/eLife.93326
Further reading
-
- Developmental Biology
Rhythmic and sequential segmentation of the growing vertebrate body relies on the segmentation clock, a multi-cellular oscillating genetic network. The clock is visible as tissue-level kinematic waves of gene expression that travel through the presomitic mesoderm (PSM) and arrest at the position of each forming segment. Here, we test how this hallmark wave pattern is driven by culturing single maturing PSM cells. We compare their cell-autonomous oscillatory and arrest dynamics to those we observe in the embryo at cellular resolution, finding similarity in the relative slowing of oscillations and arrest in concert with differentiation. This shows that cell-extrinsic signals are not required by the cells to instruct the developmental program underlying the wave pattern. We show that a cell-autonomous timing activity initiates during cell exit from the tailbud, then runs down in the anterior-ward cell flow in the PSM, thereby using elapsed time to provide positional information to the clock. Exogenous FGF lengthens the duration of the cell-intrinsic timer, indicating extrinsic factors in the embryo may regulate the segmentation clock via the timer. In sum, our work suggests that a noisy cell-autonomous, intrinsic timer drives the slowing and arrest of oscillations underlying the wave pattern, while extrinsic factors in the embryo tune this timer’s duration and precision. This is a new insight into the balance of cell-intrinsic and -extrinsic mechanisms driving tissue patterning in development.
-
- Developmental Biology
- Genetics and Genomics
Repurposing of pleiotropic factors during execution of diverse cellular processes has emerged as a regulatory paradigm. Embryonic development in metazoans is controlled by maternal factors deposited in the egg during oogenesis. Here, we explore maternal role(s) of Caspar (Casp), the Drosophila orthologue of human Fas-associated factor-1 (FAF1) originally implicated in host-defense as a negative regulator of NF-κB signaling. Maternal loss of either Casp or it’s protein partner, transitional endoplasmic reticulum 94 (TER94) leads to partial embryonic lethality correlated with aberrant centrosome behavior, cytoskeletal abnormalities, and defective gastrulation. Although ubiquitously distributed, both proteins are enriched in the primordial germ cells (PGCs), and in keeping with the centrosome problems, mutant embryos display a significant reduction in the PGC count. Moreover, the total number of pole buds is directly proportional to the level of Casp. Consistently, it’s ‘loss’ and ‘gain’ results in respective reduction and increase in the Oskar protein levels, the master determinant of PGC fate. To elucidate this regulatory loop, we analyzed several known components of mid-blastula transition and identify the translational repressor Smaug, a zygotic regulator of germ cell specification, as a potential critical target. We present a detailed structure-function analysis of Casp aimed at understanding its novel involvement during PGC development.
