title: SLIT/ROBO2 signaling promotes mammary stem cell senescence by inhibiting Wnt signaling.
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.
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, CA 95064, USA.
authors.forename: Gwyndolen
authors.initials: G
authors.lastname: Harburg
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, CA 95064, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Compton
authors.affiliation: Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, CA 95064, USA.
authors.forename: Naomi
authors.initials: N
authors.lastname: Iwai
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, CA 95064, USA.
authors.forename: Shahrzad
authors.initials: S
authors.lastname: Zada
authors.affiliation: Breakthrough Breast Cancer Unit, King's College London School of Medicine, London SE1 9RT, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Marlow
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, CA 95064, USA.
authors.forename: Phyllis
authors.initials: P
authors.lastname: Strickland
authors.affiliation: Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yi Arial
authors.initials: YA
authors.lastname: Zeng
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, CA 95064, USA. Electronic address: lhinck@ucsc.edu.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Hinck
mesh_terms: D000818:Animals; D016922:Cellular Senescence; D017353:Gene Deletion; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D042361:Mammary Glands, Human / Q000166:cytology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D000098552:Slit Homolog 2 Protein; D000097905:Roundabout Proteins
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D011971:Receptors, Immunologic; D051153:Wnt Proteins; D000098552:Slit Homolog 2 Protein; C498888:Robo2 protein, mouse; D000097905:Roundabout Proteins