Regulation of the UNC-5 netrin receptor initiates the first reorientation of migrating distal tip cells in Caenorhabditis elegans

Cell migrations play a critical role in animal development and organogenesi s. Here, we describe a mechanism by which the migration behaviour of a part icular cell type is regulated temporally and coordinated with over-all deve lopment of the organism. The hermaphrodite distal tip cells (DTCs) of Caeno rhabditis elegans migrate along the body wall in three sequential phases di stinguished by the orientation of their movements, which alternate between the anteroposterior and dorsoventral axes. The ventral-to-dorsal second mig ration 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 regulate s 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 fu nction during the longitudinal first migration phase and for a mechanism th at facilitates UNC-5 function during turning. The facilitating mechanism pr esumably does not involve transcriptional regulation of unc-5 but may repre sent an inhibition of the phase 1 mechanism that opposes or inhibits UNC-5, These results, therefore, reveal the existence of two mechanisms that regu late the UNC-5 receptor that are critical for responsiveness to the UNC-6 n etrin guidance cue and for linking the directional guidance of migrating di stal tip cells to developmental stage advancements.