Asymmetric segregation of the tumor suppressor brat regulates self-renewal in Drosophila neural stem cells
Asymmetric segregation of the tumor suppressor brat regulates self-renewal in Drosophila neural stem cells
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DOI：
10.1016/j.cell.2006.01.038
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发表时间：
2006-03-24
期刊：
影响因子：
64.5
通讯作者：
Knoblich, JA
中科院分区：
文献类型：
--
作者：
Betschinger, J;Mechtler, K;Knoblich, JA
干细胞如何产生分化和自我更新的子代细胞尚不清楚。在这里，我们证明了果蝇幼虫神经母细胞--成年大脑类似干细胞的前体--通过将生长抑制因子Brat和转录因子Propero分离到一个子细胞中来调节增殖。像普洛斯彼罗一样，Brat与适配蛋白Miranda结合并共分离。在幼虫的神经母细胞中，Brat和Propero都需要抑制两个子细胞中的一个细胞的自我更新。Propero调控细胞周期基因转录，而Brat则作为dMyc转录后抑制因子。在BRAT或PROSPERO突变体中，两个子细胞都像神经母细胞一样生长和行为，导致幼虫脑瘤的形成。类似的缺陷也见于致命的巨型幼虫(IGL)突变体，其中Brat和Prosman不是不对称的。我们已经确定了一个分子机制，可以控制自我更新，也可以防止其他干细胞中的肿瘤形成。
How stem cells generate both differentiating and self-renewing daughter cells is unclear. Here, we show that Drosophila larval neuroblasts-stem cell-like precursors of the adult brain-regulate proliferation by segregating the growth inhibitor Brat and the transcription factor Prospero into only one daughter cell. Like Prospero, Brat binds and cosegregates with the adaptor protein Miranda. In larval neuroblasts, both Brat and Prospero are required to inhibit self-renewal in one of the two daughter cells. While Prospero regulates cell-cycle gene transcription, Brat acts as a posttranscriptional inhibitor of dMyc. In brat or prospero mutants, both daughter cells grow and behave like neuroblasts leading to the formation of larval brain tumors. Similar defects are seen in lethal giant larvae, (Igl) mutants where Brat and Prospero are not asymmetric. We have identified a molecular mechanism that may control self-renewal and prevent tumor formation in other stem cells as well.