SLIT/ROBO2 signaling promotes mammary stem cell senescence by inhibiting Wnt signaling.
SLIT/ROBO2 signaling promotes mammary stem cell senescence by inhibiting Wnt signaling.
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DOI：
10.1016/j.stemcr.2014.07.007
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发表时间：
2014-09-09
影响因子：
5.9
通讯作者：
Hinck, Lindsay
中科院分区：
文献类型：
--
作者：
Harburg, Gwyndolen;Compton, Jennifer;Liu, Wei;Iwai, Naomi;Zada, Shahrzad;Marlow, Rebecca;Strickland, Phyllis;Zeng, Yi Arial;Hinck, Lindsay
WNT信号刺激许多类型的成体干细胞（包括乳腺干细胞（MaSC））的自我更新，但限制这种活性的机制知之甚少。在这里，我们证明了SLIT 2通过ROBO 2在基底细胞亚群中的信号传导来负调节WNT信号传导，从而限制干细胞更新。SLIT/ROB 0 2信号传导的缺乏导致核β-连环蛋白水平的增加。Robo 2的丢失不会增加干细胞的数量;相反，在SLIT/ROBO 2信号转导不存在的情况下，干细胞更新得到增强。这是由于p16 INK 4a的抑制表达，这反过来又延迟了MaSC衰老。总之，我们的研究支持一个模型，其中SLIT通过对抗WNT的活动和限制自我更新来限制MaSCs的扩张。SLIT/ROBO 2信号传导增加p16 INK 4a表达，促进细胞衰老SLIT/ROBO 2信号传导的丧失增强乳腺连续移植性在这篇文章中，Hinck和同事表明，SLIT 2通过ROBO 2信号传导和对抗WNT信号传导来限制干细胞更新。这导致p16 INK 4a的表达增加，促进细胞衰老。
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 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. 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 In this article, Hinck and colleagues show that SLIT2 restricts stem cell renewal by signaling through ROBO2 and opposing WNT signaling. This results in increased expression of p16INK4a, promoting cellular senescence.
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