HHMI and Kimmel Center for Biology and Medicine of the Skirball Institute, Department of Cell Biology, New York University School of Medicine, New York, NY, USA.
Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
Nat Commun. 2020 Sep 8;11(1):4477. doi: 10.1038/s41467-020-18185-2.
Individual cells detach from cohesive ensembles during development and can inappropriately separate in disease. Although much is known about how cells separate from epithelia, it remains unclear how cells disperse from clusters lacking apical-basal polarity, a hallmark of advanced epithelial cancers. Here, using live imaging of the developmental migration program of Drosophila primordial germ cells (PGCs), we show that cluster dispersal is accomplished by stabilizing and orienting migratory forces. PGCs utilize a G protein coupled receptor (GPCR), Tre1, to guide front-back migratory polarity radially from the cluster toward the endoderm. Posteriorly positioned myosin-dependent contractile forces pull on cell-cell contacts until cells release. Tre1 mutant cells migrate randomly with transient enrichment of the force machinery but fail to separate, indicating a temporal contractile force threshold for detachment. E-cadherin is retained on the cell surface during cell separation and augmenting cell-cell adhesion does not impede detachment. Notably, coordinated migration improves cluster dispersal efficiency by stabilizing cell-cell interfaces and facilitating symmetric pulling. We demonstrate that guidance of inherent migratory forces is sufficient to disperse cell clusters under physiological settings and present a paradigm for how such events could occur across development and disease.
个体细胞在发育过程中会从细胞团中脱离，如果发生疾病，这些细胞可能会异常分离。尽管人们已经了解了细胞如何从上皮组织中分离，但细胞如何从缺乏顶端-基底极性的细胞簇中扩散出去，仍然是一个未解之谜，而顶端-基底极性是高级上皮癌的一个标志。在这里，我们通过对果蝇原始生殖细胞（PGC）发育迁移程序的实时成像，发现细胞簇的分散是通过稳定和定向迁移力来实现的。PGC 利用 G 蛋白偶联受体（GPCR）Tre1 从细胞簇向肠内胚层引导前后向迁移极性。位于后部的肌球蛋白依赖性收缩力拉动细胞-细胞连接处，直到细胞释放。Tre1 突变体细胞随机迁移，短暂富集力机制，但无法分离，表明分离需要一个暂时的收缩力阈值。在细胞分离过程中，E-钙粘蛋白保留在细胞表面，增加细胞-细胞粘附并不会阻碍分离。值得注意的是，协调的迁移通过稳定细胞-细胞界面和促进对称牵拉，提高了细胞簇的分散效率。我们证明，在生理条件下，固有迁移力的引导足以分散细胞簇，并为这些事件如何在发育和疾病过程中发生提供了一个范例。
