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Cell Rep. 2015 Oct 13;13(2):290-301. doi: 10.1016/j.celrep.2015.09.006. Epub 2015 Oct 1.

Mammary Stem Cell Self-Renewal Is Regulated by Slit2/Robo1 Signaling through SNAI1 and mINSC.

Author information

1
Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
2
Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064, USA; Department of Biology, California State University Channel Islands, Camarillo, CA 93012, USA.
3
Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
4
Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064, USA. Electronic address: lhinck@ucsc.edu.

Abstract

Tissue homeostasis requires somatic stem cell maintenance; however, mechanisms regulating this process during organogenesis are not well understood. Here, we identify asymmetrically renewing basal and luminal stem cells in the mammary end bud. We demonstrate that SLIT2/ROBO1 signaling regulates the choice between self-renewing asymmetric cell divisions (ACDs) and expansive symmetric cell divisions (SCDs) by governing Inscuteable (mInsc), a key member of the spindle orientation machinery, through the transcription factor Snail (SNAI1). Loss of SLIT2/ROBO1 signaling increases SNAI1 in the nucleus. Overexpression of SNAI1 increases mInsc expression, an effect that is inhibited by SLIT2 treatment. Increased mInsc does not change cell proliferation in the mammary gland (MG) but instead causes more basal cap cells to divide via SCD, at the expense of ACD, leading to more stem cells and larger outgrowths. Together, our studies provide insight into how the number of mammary stem cells is regulated by the extracellular cue SLIT2.

KEYWORDS:

Inscuteable; ROBO; SLIT; SNAIL; asymmetric cell division; breast; mammary stem cell

PMID:
26440891
PMCID:
PMC4606466
DOI:
10.1016/j.celrep.2015.09.006
[Indexed for MEDLINE]
Free PMC Article

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