Notch Signaling Regulates Mammary Stem Cell Function and Luminal Cell-Fate Commitment
Notch Signaling Regulates Mammary Stem Cell Function and Luminal Cell-Fate Commitment
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DOI：
10.1016/j.stem.2008.08.001
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发表时间：
2008-10-09
期刊：
影响因子：
23.9
通讯作者：
Visvader, Jane E.
中科院分区：
文献类型：
--
作者：
Bouras, Toula;Pal, Bhupinder;Visvader, Jane E.
小鼠乳腺干细胞及其祖细胞亚群的鉴定为研究其谱系特化和分化的遗传控制提供了前景。在这里，我们探讨了Notch通路在乳腺上皮层次结构中的作用。我们表明，在MaSC富集群体中敲低经典Notch效应子Cbf-1导致体内干细胞活性增加以及异常末端芽的形成，这意味着内源性Notch信号传导在限制MaSC扩增中的作用。相反，发现Notch在体内优先在导管腔上皮中活化，并且仅沿着腔谱系促进MaSC的定型。值得注意的是，组成型Notch信号传导特异性靶向管腔祖细胞用于扩增，导致增生和肿瘤发生。这些发现揭示了Notch信号传导在MaSC和管腔细胞定型中的关键作用，并进一步表明不适当的Notch活化促进管腔祖细胞的自我更新和转化。
The recent identification of mouse mammary stem cells (MaSCs) and progenitor subpopulations has enhanced the prospect of investigating the genetic control of their lineage specification and differentiation. Here we have explored the role of the Notch pathway within the mammary epithelial hierarchy. We show that knockdown of the canonical Notch effector Cbf-1 in the MaSC-enriched population results in increased stem cell activity in vivo as well as the formation of aberrant end buds, implying a role for endogenous Notch signaling in restricting MaSC expansion. Conversely, Notch was found to be preferentially activated in the ductal luminal epithelium in vivo and promoted commitment of MaSCs exclusively along the luminal lineage. Notably, constitutive Notch signaling specifically targeted luminal progenitor cells for expansion, leading to hyperplasia and tumorigenesis. These findings reveal key roles for Notch signaling in MaSCs and luminal cell commitment and further suggest that inappropriate Notch activation promotes the self-renewal and transformation of luminal progenitor cells.