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

Abstract

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.

Slit-Robo signaling

“…A higher amount of symmetric division in turn leads to increased self-renewal of the stem cell population and mammary outgrowth. Although Robo2 does not play a role in this context, it has been shown to regulate the senescence of mammary stem cells by inhibiting Wnt signaling (Harburg et al, 2014). Interestingly, these two studies highlight different signaling outputs via different receptors by a single ligand, Slit2.…”

Regulation and plasticity of intestinal stem cells during homeostasis and regeneration

“…(Azzolin et al, 2014;Gregorieff et al, 2015) signaling (Zhang et al, 2015). Paradoxically, signaling through Slit2/Robo2 decreases β-catenin in mammary stem cells, limiting stem cell self-renewal (Harburg et al, 2014). Future studies are clearly required to dissect downstream targets of Slit2 activity in intestinal regeneration.…”

The Islet Confidential: Recent Trends and Perspectives in Pancreatic Islet Transplantation

“…Attention must be given to the encapsulation and crosslinking materials, as they must remain inert in the long run and should not lead to any immune responses. Considerable evidences suggest [70][71][72][73][74][75][76][77][78] the association of pancreatic β cells with other networks, indicating certain 'cross-talks' among the heterodermal derivatives. These studies warn that the islets, albeit unique, are not isolated entities, but are in continuous equilibrium with other physiological systems.…”