The Gurdon Institute and The Department of Genetics, University of Cambridge, Tennis Court Rd, Cambridge CB2 1QN, UK.
The Gurdon Institute and The Department of Genetics, University of Cambridge, Tennis Court Rd, Cambridge CB2 1QN, UK
Development. 2019 Jan 18;146(2):dev168963. doi: 10.1242/dev.168963.
The timing of egg chamber development is controlled by a germline Delta signal that activates Notch in the follicle cells to induce them to cease proliferation and differentiate. Here, we report that follicle cells lacking the RNA-binding protein IMP go through one extra division owing to a delay in the Delta-dependent S2 cleavage of Notch. The timing of Notch activation has previously been shown to be controlled by cis-inhibition by Delta in the follicle cells, which is relieved when the miRNA pathway represses Delta expression. mutants are epistatic to mutants and give an additive phenotype with and mutants, indicating that IMP functions independently of both cis-inhibition and the miRNA pathway. We find that the phenotype is rescued by overexpression of Kuzbanian, the metalloprotease that mediates the Notch S2 cleavage. Furthermore, Kuzbanian is not enriched at the apical membrane in mutants, accumulating instead in late endosomes. Thus, IMP regulates Notch signalling by controlling the localisation of Kuzbanian to the apical domain, where Notch cleavage occurs, revealing a novel regulatory step in the Notch pathway.
卵室发育的时间由生殖系 Delta 信号控制，该信号激活滤泡细胞中的 Notch，使其停止增殖并分化。在这里，我们报告说，由于 Delta 依赖性 S2 切割 Notch 的延迟，缺乏 RNA 结合蛋白 IMP 的滤泡细胞经历了一次额外的分裂。 Notch 的激活时间以前被证明受滤泡细胞中 Delta 的顺式抑制控制，当 miRNA 途径抑制 Delta 表达时，这种抑制就会被解除。 突变体与 突变体是上位性的，并且与 和 突变体具有加性表型，表明 IMP 独立于顺式抑制和 miRNA 途径发挥作用。我们发现，过表达介导 Notch S2 切割的金属蛋白酶 Kuzbanian 可以挽救 表型。此外，在 突变体中，Kuzbanian 没有富集在顶端膜上，而是积累在晚期内体中。因此，IMP 通过控制 Kuzbanian 定位到发生 Notch 切割的顶端域来调节 Notch 信号，揭示了 Notch 途径中的一个新的调节步骤。
