SLIT/ROBO2 Signaling Promotes Mammary Stem Cell Senescence by Inhibiting Wnt Signaling

•SLIT2 opposes WNT signaling to act as a mammary stem cell nonrenewal factor•SLIT/ROBO2 signaling increases p16INK4a expression, promoting cellular senescence•Loss of SLIT/ROBO2 signaling enhances mammary gland serial transplantability

SummaryWNT 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 p16INK4a, 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.

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