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

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 negat...

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Detalles Bibliográficos
Autores principales: Harburg, Gwyndolen, Compton, Jennifer, Liu, Wei, Iwai, Naomi, Zada, Shahrzad, Marlow, Rebecca, Strickland, Phyllis, Zeng, Yi Arial, Hinck, Lindsay
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266005/
https://www.ncbi.nlm.nih.gov/pubmed/25241737
http://dx.doi.org/10.1016/j.stemcr.2014.07.007
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author Harburg, Gwyndolen
Compton, Jennifer
Liu, Wei
Iwai, Naomi
Zada, Shahrzad
Marlow, Rebecca
Strickland, Phyllis
Zeng, Yi Arial
Hinck, Lindsay
author_facet Harburg, Gwyndolen
Compton, Jennifer
Liu, Wei
Iwai, Naomi
Zada, Shahrzad
Marlow, Rebecca
Strickland, Phyllis
Zeng, Yi Arial
Hinck, Lindsay
author_sort Harburg, Gwyndolen
collection PubMed
description 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.
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spelling pubmed-42660052014-12-16 SLIT/ROBO2 Signaling Promotes Mammary Stem Cell Senescence by Inhibiting Wnt Signaling Harburg, Gwyndolen Compton, Jennifer Liu, Wei Iwai, Naomi Zada, Shahrzad Marlow, Rebecca Strickland, Phyllis Zeng, Yi Arial Hinck, Lindsay Stem Cell Reports Report 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. Elsevier 2014-08-28 /pmc/articles/PMC4266005/ /pubmed/25241737 http://dx.doi.org/10.1016/j.stemcr.2014.07.007 Text en © 2014 The Authors http://creativecommons.org/licenses/by-nc-nd/3.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
spellingShingle Report
Harburg, Gwyndolen
Compton, Jennifer
Liu, Wei
Iwai, Naomi
Zada, Shahrzad
Marlow, Rebecca
Strickland, Phyllis
Zeng, Yi Arial
Hinck, Lindsay
SLIT/ROBO2 Signaling Promotes Mammary Stem Cell Senescence by Inhibiting Wnt Signaling
title SLIT/ROBO2 Signaling Promotes Mammary Stem Cell Senescence by Inhibiting Wnt Signaling
title_full SLIT/ROBO2 Signaling Promotes Mammary Stem Cell Senescence by Inhibiting Wnt Signaling
title_fullStr SLIT/ROBO2 Signaling Promotes Mammary Stem Cell Senescence by Inhibiting Wnt Signaling
title_full_unstemmed SLIT/ROBO2 Signaling Promotes Mammary Stem Cell Senescence by Inhibiting Wnt Signaling
title_short SLIT/ROBO2 Signaling Promotes Mammary Stem Cell Senescence by Inhibiting Wnt Signaling
title_sort slit/robo2 signaling promotes mammary stem cell senescence by inhibiting wnt signaling
topic Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266005/
https://www.ncbi.nlm.nih.gov/pubmed/25241737
http://dx.doi.org/10.1016/j.stemcr.2014.07.007
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