Su M, Merz D C, Killeen M T, Zhou Y, Zheng H, Kramer J M, Hedgecock E M, Culotti J G
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. M5S 1A8, Canada.
Development. 2000 Feb;127(3):585-94. doi: 10.1242/dev.127.3.585.
Cell migrations play a critical role in animal development and organogenesis. Here, we describe a mechanism by which the migration behaviour of a particular cell type is regulated temporally and coordinated with over-all development of the organism. The hermaphrodite distal tip cells (DTCs) of Caenorhabditis elegans migrate along the body wall in three sequential phases distinguished by the orientation of their movements, which alternate between the anteroposterior and dorsoventral axes. The ventral-to-dorsal second migration phase requires the UNC-6 netrin guidance cue and its receptors UNC-5 and UNC-40, as well as additional, UNC-6-independent guidance systems. We provide evidence that the transcriptional upregulation of unc-5 in the DTCs is coincident with the initiation of the second migration phase, and that premature UNC-5 expression in these cells induces precocious turning in an UNC-6-dependent manner. The DAF-12 steroid hormone receptor, which regulates developmental stage transitions in C. elegans, is required for initiating the first DTC turn and for coincident unc-5 upregulation. We also present evidence for the existence of a mechanism that opposes or inhibits UNC-5 function during the longitudinal first migration phase and for a mechanism that facilitates UNC-5 function during turning. The facilitating mechanism presumably does not involve transcriptional regulation of unc-5 but may represent an inhibition of the phase 1 mechanism that opposes or inhibits UNC-5. These results, therefore, reveal the existence of two mechanisms that regulate the UNC-5 receptor that are critical for responsiveness to the UNC-6 netrin guidance cue and for linking the directional guidance of migrating distal tip cells to developmental stage advancements.
细胞迁移在动物发育和器官形成过程中发挥着关键作用。在此，我们描述了一种机制，通过该机制特定细胞类型的迁移行为在时间上受到调控，并与生物体的整体发育相协调。秀丽隐杆线虫的雌雄同体远端末梢细胞（DTCs）沿体壁分三个连续阶段迁移，这些阶段以其运动方向区分，运动方向在前-后轴和背-腹轴之间交替。从腹侧到背侧的第二个迁移阶段需要UNC-6网蛋白引导信号及其受体UNC-5和UNC-40，以及其他不依赖UNC-6的引导系统。我们提供的证据表明，DTCs中unc-5的转录上调与第二个迁移阶段的开始同时发生，并且这些细胞中过早的UNC-5表达以依赖UNC-6的方式诱导早熟转向。DAF-12类固醇激素受体调节秀丽隐杆线虫的发育阶段转变，是启动第一次DTC转向和同时上调unc-5所必需的。我们还提供了证据，证明在纵向的第一个迁移阶段存在一种对抗或抑制UNC-5功能的机制，以及在转向过程中促进UNC-5功能的机制。促进机制可能不涉及unc-5的转录调控，但可能代表对对抗或抑制UNC-5的第一阶段机制的抑制。因此，这些结果揭示了存在两种调节UNC-5受体的机制，这两种机制对于响应UNC-6网蛋白引导信号以及将迁移的远端末梢细胞的定向引导与发育阶段进展相联系至关重要。
