Developmental biology - Puberty & Stem Cells|
Sleeping Mammary Stem Cells Wake Up In Puberty
Researchers have discovered how the growth of milk-producing mammary glands is triggered during puberty...
Stem cells in the mammary gland remain quiet until stimulated to awaken by the protein FoxP1, according to new research from the Walter and Eliza Hall Institute published in the journal Developmental Cell.
The research expands our knowledge of how mammary glands - a component of the human breast - develop from stem cells. The discovery of FoxP1, underpins a new understanding of how defects in this process can lead to breast cancer. The research was led by Nai Yang Fu PhD, Professor Jane Visvader and Professor Geoff Lindeman, medical oncologist at the Royal Melbourne Hospital and Peter MacCallum Cancer Centre, in collaboration with Professor Gordon Smyth and his bioinformatics team.
Stem cells are cells that give rise to a wide range of cells types - yet often lie dormant in our body. Little is known about how these 'sleeping' cells wake into an active state until the discovery of the FoxP1 gene. This gene appears to trigger 'awakening' via the rapid growth and development of mammary glands. Without FoxP1, mammary stem cells remain locked in a dormant state and mammary glands do not grow.
WAKING UP STEM CELLS
According to Jane Visvader PhD, in puberty stem cells receive the order driving their rapid expansion. FoxP1 switches off the production of other cellular proteins by repressing those proteins' genes.
"A gene called FoxP1 is essential to making this signal happen in an adult. We discovered that FoxP1 switches off the production of one of the key proteins keeping mammary stem cells asleep. As the level of this protein drops, stem cells wake up and begin to divide, driving mammary gland growth," Dr Fu explains.
"This project brought together expertise in cell biology, developmental biology, bioinformatics and imaging to solve the question of how mammary stem cells wake up in puberty and affect breast tissue. We are still looking for the precise connections linking female hormones and FoxP1, but we are one step closer to understanding the detailed process of breast development. This is also helping us connect faulty cells that contribute to breast development with the development of breast cancer."
Jane E. Visvader PhD, Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research; Department of Medical Biology, The University of Melbourne, Parkville, Australia.
• Foxp1 is an essential transcription factor for mammary gland development
• Foxp1 controls the activation of quiescent MaSCs marked by Tspan8
• Foxp1 directly represses the transcription of Tspan8 in basal, but not luminal, cells
• Tspan8 deletion rescues the Foxp1-deficient mammary phenotype
Long-lived quiescent mammary stem cells (MaSCs) are presumed to coordinate the dramatic expansion of ductal epithelium that occurs through the different phases of postnatal development, but little is known about the molecular regulators that underpin their activation. We show that ablation of the transcription factor Foxp1 in the mammary gland profoundly impairs ductal morphogenesis, resulting in a rudimentary tree throughout life. Foxp1-deficient glands were highly enriched for quiescent Tspan8hi MaSCs, which failed to become activated even in competitive transplantation assays, thus highlighting a cell-intrinsic defect. Foxp1 deletion also resulted in aberrant expression of basal genes in luminal cells, inferring a role in cell-fate decisions. Notably, Foxp1 was uncovered as a direct repressor of Tspan8 in basal cells, and deletion of Tspan8 rescued the defects in ductal morphogenesis elicited by Foxp1 loss. Thus, a single transcriptional regulator Foxp1 can control the exit of MaSCs from dormancy to orchestrate differentiation and development.
Nai Yang Fu, Bhupinder Pal, Yunshun Chen, Felicity C. Jackling, Michael Milevskiy, François Vaillant, Bianca D. Capaldo, Fusheng Guo, Kevin H. Liu, Anne C. Rios, Nicholas Lim, Andrew J. Kueh, David M. Virshup, Marco J. Herold, Haley O. Tucker, Gordon K. Smyth, Geoffrey J. Lindeman and Jane E. Visvader.
About the Journal of Biological Chemistry
The research was supported by the Australian National Health and Medical Research Council, the Australian Cancer Research Foundation, Cure Cancer Australia, the National Breast Cancer Foundation, the Victorian Cancer Agency and the Victorian Government.
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Oct 26, 2018 Fetal Timeline Maternal Timeline News News Archive
High resolution imaging of mammary gland ducts - was critical to the discovery of how
their growth is triggered in puberty. Credit: Walter and Eliza Hall Institute, Australia