DiBella Linda M, Park Alice, Sun Zhaoxia
Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
Hum Mol Genet. 2009 Feb 15;18(4):595-606. doi: 10.1093/hmg/ddn384. Epub 2008 Nov 13.
The cell surface organelle called the cilium is essential for preventing kidney cyst formation and for establishing left-right asymmetry of the vertebrate body plan. Recent advances suggest that the cilium functions as a sensory organelle in vertebrate cells for multiple signaling pathways such as the hedgehog and the Wnt pathways. Prompted by kidney cyst formation in tuberous sclerosis complex (TSC) patients and rodent models, we investigated the role of the cilium in the TSC-target of rapamycin (TOR) pathway using zebrafish. TSC1 and TSC2 genes are causal for TSC, and their protein products form a complex in the TOR pathway that integrates environmental signals to regulate cell growth, proliferation and survival. Two TSC1 homologs were identified in zebrafish, which we refer to as tsc1a and tsc1b. Morpholino knockdown of tsc1a led to a ciliary phenotype including kidney cyst formation and left-right asymmetry defects. Tsc1a was observed to localize to the Golgi, but morpholinos against it, nonetheless, acted synthetically with ciliary genes in producing kidney cysts. Consistent with a role of the cilium in the same pathway as Tsc genes, the TOR pathway is aberrantly activated in ciliary mutants, resembling the effect of tsc1a knockdown. Moreover, kidney cyst formation in ciliary mutants was blocked by the Tor inhibitor, rapamycin. Surprisingly, we observed elongation of cilia in tsc1a knockdown animals. Together, these data suggest a signaling network between the cilium and the TOR pathway in that ciliary signals can feed into the TOR pathway and that Tsc1a regulates the length of the cilium itself.
被称为纤毛的细胞表面细胞器对于预防肾囊肿形成以及确立脊椎动物身体结构的左右不对称性至关重要。最近的研究进展表明，纤毛在脊椎动物细胞中作为一种感觉细胞器，参与多种信号通路，如刺猬信号通路和Wnt信号通路。受结节性硬化症（TSC）患者和啮齿动物模型中肾囊肿形成的启发，我们利用斑马鱼研究了纤毛在TSC-雷帕霉素靶蛋白（TOR）信号通路中的作用。TSC1和TSC2基因是导致TSC的病因，它们的蛋白质产物在TOR信号通路中形成一个复合物，整合环境信号以调节细胞生长、增殖和存活。在斑马鱼中鉴定出两个TSC1同源物，我们将其称为tsc1a和tsc1b。对tsc1a进行吗啉代敲低会导致一种纤毛表型，包括肾囊肿形成和左右不对称缺陷。观察到Tsc1a定位于高尔基体，但针对它的吗啉代仍与纤毛基因在产生肾囊肿方面具有协同作用。与纤毛在与Tsc基因相同的信号通路中发挥作用一致，TOR信号通路在纤毛突变体中异常激活，类似于tsc1a敲低的效果。此外，纤毛突变体中的肾囊肿形成被TOR抑制剂雷帕霉素阻断。令人惊讶的是，我们在tsc1a敲低的动物中观察到纤毛伸长。总之，这些数据表明纤毛和TOR信号通路之间存在一个信号网络，即纤毛信号可以传入TOR信号通路，并且Tsc1a调节纤毛自身的长度。
