One or more of these could explain the migration defect phenotype observed in hypoxic embryos: An intrinsic loss of cell motility, leaving PGCs unable to respond to extrinsic migratory cues; an intrinsic failure to correctly interpret extrinsic cues; defective development or death of somatic cells that provide guidance cues to migratory PGCs; and improper cell-cell adhesion between PGCs and somatic cells. The time-lapse videos showed that mis-migrated ectopic PGCs were able to move, thus PGC migration defect could not be a consequence of cell immotility. Regulation of CXCR4 expression by hypoxia may be essential for directing PGC migration. It has been reported that hypoxic preconditioning induces CXCR4 expression in mesenchymal stell cells. However, our video shows that only PGCs that are near the posterior side cannot migrate towards the intermediate target during gastrulation. It is Ruxolitinib unclear why only those PGCs cannot migrate correctly. Therefore, the second possibility could also be ruled out. The third possibility is that under hypoxia defective development or death of somatic cells provides guidance cues to migratory PGCs. As reported, the major biological effects of the chemokine SDF-1a are related to its ability to induce motility, chemotactic responses and adhesion in cells bearing cognate CXCR4. Cells bearing CXCR4 always respond to a SDF-1 gradient produced by somatic cells. If hypoxia disrupts the SDF-1 gradient produced by somatic cells in the intermediate target, it is possible that only the PGC that are close to the intermediate target would respond to this cue, while PGCs distant from the intermediate target would fail to do so. Future studies are required to investigate this possibility. The fourth possibility, improper cell-cell adhesion between PGCs and somatic cells, could also explain PGC migration defect during gastrulation. It is suggested that the PGC movement to the intermediate target during gastrulation depends on general gastrulation movement. The segregation of individual cells from the tissues where they originally reside requires alterations in their adhesive properties. Modulations of cell-cell interactions leading to cell detachment and invasion of neighboring tissues has been shown to promote dispersion of tumor cells and to be essential for morphogenesis during normal development. A molecule known to play a critical role in controlling cell-cell adhesion in such biological contexts is the calcium-dependent cell adhesion molecule, E-cadherin. It has been shown that the level of membranal E-cadherin is modulated during early PGC development and reduction in E-cadherin is important for PGC motility. E-cadherin is down-regulated on the membrane of PGCs upon the onset of migration and its expression persists. However, a high level of E-cadherin makes PGC immotile. It has been reported that E-cadherin downregulation is induced by hypoxia in trophoblast cells and in ovarian carcinoma cells. Therefore, it is possible that hypoxia alters PGC membranal E-cadherin level. Tumor populations need to overcome distinct microenvironmental barriers prior to metastasizing to other organs.