Notch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells
Notch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells
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DOI：
10.1242/dev.070763
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发表时间：
2012-02-01
期刊：
影响因子：
4.6
通讯作者：
Samuelson, Linda C.
中科院分区：
文献类型：
--
作者：
VanDussen, Kelli L.;Carulli, Alexis J.;Samuelson, Linda C.
众所周知，Notch 信号传导可调节肠干细胞和祖细胞的增殖和分化。然而，Notch 信号的直接细胞目标和具体功能尚未确定。我们在小鼠身上展示了 Notch 直接靶向隐窝基底柱状 (CBC) 细胞以维持干细胞活性。 Notch 抑制导致 CBC 细胞快速损失，增殖减少、细胞凋亡和类器官启动效率降低。此外，CBC干细胞特异性标记Olfm4的表达直接依赖于Notch信号传导，转录通过启动子中的RBP-J kappa结合位点激活。 Notch抑制还导致上皮祖细胞过早分化为分泌细胞类型，包括表达潘氏细胞和杯状细胞标记物的大量细胞。对Atoh1缺陷肠道中Notch功能的分析表明，细胞变化依赖于Atoh1，而Notch对Olfm4基因表达的调节不依赖于Atoh1。我们的研究结果表明，Notch 针对不同的祖细胞群来维持成体肠道干细胞并调节细胞命运选择以控制上皮细胞稳态。
Notch signaling is known to regulate the proliferation and differentiation of intestinal stem and progenitor cells; however, direct cellular targets and specific functions of Notch signals had not been identified. We show here in mice that Notch directly targets the crypt base columnar (CBC) cell to maintain stem cell activity. Notch inhibition induced rapid CBC cell loss, with reduced proliferation, apoptotic cell death and reduced efficiency of organoid initiation. Furthermore, expression of the CBC stem cell-specific marker Olfm4 was directly dependent on Notch signaling, with transcription activated through RBP-J kappa binding sites in the promoter. Notch inhibition also led to precocious differentiation of epithelial progenitors into secretory cell types, including large numbers of cells that expressed both Paneth and goblet cell markers. Analysis of Notch function in Atoh1-deficient intestine demonstrated that the cellular changes were dependent on Atoh1, whereas Notch regulation of Olfm4 gene expression was Atoh1 independent. Our findings suggest that Notch targets distinct progenitor cell populations to maintain adult intestinal stem cells and to regulate cell fate choice to control epithelial cell homeostasis.