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Stem Cell Reports. 2014 Sep 9;3(3):385-93. doi: 10.1016/j.stemcr.2014.07.007. Epub 2014 Aug 28.

SLIT/ROBO2 signaling promotes mammary stem cell senescence by inhibiting Wnt signaling.

Author information

1
Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, CA 95064, USA.
2
Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.
3
Breakthrough Breast Cancer Unit, King's College London School of Medicine, London SE1 9RT, UK.
4
Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, CA 95064, USA. Electronic address: lhinck@ucsc.edu.

Abstract

WNT signaling stimulates the self-renewal of many types of adult stem cells, including mammary stem cells (MaSCs), but mechanisms that limit this activity are poorly understood. Here, we demonstrate that SLIT2 restricts stem cell renewal by signaling through ROBO2 in a subset of basal cells to negatively regulate WNT signaling. The absence of SLIT/ROBO2 signaling leads to increased levels of nuclear β-catenin. Robo2 loss does not increase the number of stem cells; instead, stem cell renewal is enhanced in the absence of SLIT/ROBO2 signaling. This is due to repressed expression of p16(INK4a), which, in turn, delays MaSC senescence. Together, our studies support a model in which SLITs restrict the expansion of MaSCs by countering the activity of WNTs and limiting self-renewal.

PMID:
25241737
PMCID:
PMC4266005
DOI:
10.1016/j.stemcr.2014.07.007
[Indexed for MEDLINE]
Free PMC Article

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