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Dev Cell. 2018 Dec 3;47(5):629-644.e8. doi: 10.1016/j.devcel.2018.10.001. Epub 2018 Oct 25.

Foxp1 Is Indispensable for Ductal Morphogenesis and Controls the Exit of Mammary Stem Cells from Quiescence.

Author information

1
Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore 169857, Singapore. Electronic address: naiyang.fu@duke-nus.edu.sg.
2
Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia.
3
Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
4
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore 169857, Singapore.
5
Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; Prinses Máxima Center for Pediatric Oncology, Hubrecht Institute, Uppsalalaan 8, Utrecht 3584 CT, the Netherlands.
6
Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; Division of Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
7
Molecular Biosciences and Institute for Molecular and Cellular Biology, University of Texas at Austin, Austin, TX, USA.
8
Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; School of Mathematics and Statistics, The University of Melbourne, Parkville, VIC 3010, Australia.
9
Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; The Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Parkville, VIC 3050, Australia; Department of Medicine, The University of Melbourne, Parkville, VIC 3010, Australia.
10
Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: visvader@wehi.edu.au.

Abstract

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.

KEYWORDS:

Fox transcription factors; Foxp1; Lgr5; Tetraspanin; Tspan8; Wnt; mammary gland development; mammary stem cell; quiescence

PMID:
30523786
DOI:
10.1016/j.devcel.2018.10.001
[Indexed for MEDLINE]
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