Institut Pasteur, Developmental Biology Department, F-75015 Paris, France.
Development. 2011 Nov;138(21):4585-95. doi: 10.1242/dev.065292. Epub 2011 Sep 28.
Tight regulation of self-renewal and differentiation of adult stem cells ensures that tissues are properly maintained. In the Drosophila intestine, both commitment, i.e. exit from self-renewal, and terminal differentiation are controlled by Notch signaling. Here, we show that distinct requirements for Notch activity exist: commitment requires high Notch activity, whereas terminal differentiation can occur with lower Notch activity. We identified the gene GDP-mannose 4,6-dehydratase (Gmd), a modulator of Notch signaling, as being required for commitment but dispensable for terminal differentiation. Gmd loss resulted in aberrant, self-renewing stem cell divisions that generated extra ISC-like cells defective in Notch reporter activation, as well as wild-type-like cell divisions that produced properly terminally differentiated cells. Lowering Notch signaling using additional genetic means, we provided further evidence that commitment has a higher Notch signaling requirement than terminal differentiation. Our work suggests that a commitment requirement for high-level Notch activity safeguards the stem cells from loss through differentiation, revealing a novel role for the importance of Notch signaling levels in this system.
成体干细胞的自我更新和分化受到严格调控，以确保组织正常维持。在果蝇的肠道中，细胞的定型（即退出自我更新）和终末分化均受到 Notch 信号的调控。在这里，我们发现 Notch 活性存在不同的需求：定型需要高 Notch 活性，而终末分化可以在较低的 Notch 活性下进行。我们发现 GDP-甘露糖 4,6-脱水酶（Gmd）是 Notch 信号的调节剂，它是定型所必需的，但对终末分化是可有可无的。Gmd 的缺失导致了异常的、自我更新的干细胞分裂，产生了缺乏 Notch 报告基因激活的多余 ISC 样细胞，以及产生正常终末分化细胞的野生型样细胞分裂。通过其他遗传手段降低 Notch 信号，我们提供了进一步的证据表明定型比终末分化需要更高水平的 Notch 信号。我们的工作表明，定型需要高水平的 Notch 活性，这可以防止干细胞通过分化而丢失，揭示了 Notch 信号水平在这个系统中的一个新作用。
