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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cellular Senescence
  • Gene Deletion
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Mammary Glands, Human / cytology
  • Mice
  • Nerve Tissue Proteins / metabolism*
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • Signal Transduction*
  • Stem Cells / cytology*
  • Stem Cells / metabolism
  • Wnt Proteins / metabolism*


  • Intercellular Signaling Peptides and Proteins
  • Nerve Tissue Proteins
  • Receptors, Immunologic
  • Robo2 protein, mouse
  • Wnt Proteins
  • Slit homolog 2 protein