McDonald Jocelyn A, Khodyakova Anna, Aranjuez George, Dudley Colleen, Montell Denise J
Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Curr Biol. 2008 Nov 11;18(21):1659-67. doi: 10.1016/j.cub.2008.09.041. Epub 2008 Oct 30.
Many cells that migrate during normal embryonic development or in metastatic cancer first detach from an epithelium. However, this step is often difficult to observe directly in vivo, and the mechanisms controlling the ability of cells to leave the epithelium are poorly understood. In addition, once cells detach, they must assume a migratory phenotype, involving changes in cytoskeletal and signaling dynamics. Drosophila border cells provide a model system in which a combination of forward genetics and live-cell imaging can allow researchers to investigate the cellular and molecular mechanisms of epithelial cell detachment and migration in vivo.
We identified the Drosophila homolog of the serine/threonine kinase PAR-1 (MARK/Kin1) in a screen for mutations that disrupt border cell migration. Previous studies identified two proteins, Apontic and Notch, that indirectly affect border cell detachment by regulating transcription of downstream targets. In contrast, PAR-1 directly modulates apical-basal polarity between border cells and epithelial cells to promote detachment. Furthermore, PAR-1, but not the apical polarity complex protein PAR-3, promotes the directionality of transient cell protrusions, which border cells require for sensing the chemoattractant gradient.
We conclude that PAR-1-dependent apical-basal polarity is required for proper detachment of migratory border cells from neighboring epithelial cells. Moreover, polarity controlled by PAR-1 influences the ability of migratory cells to sense direction, a critical feature of migration. Thus, this work reveals new insights into two distinct, but essential, steps of epithelial cell migration.
许多在正常胚胎发育过程中或转移性癌症中迁移的细胞首先从上皮组织脱离。然而，这一步骤在体内往往难以直接观察到，并且控制细胞脱离上皮组织能力的机制也知之甚少。此外，一旦细胞脱离，它们必须呈现迁移表型，这涉及细胞骨架和信号动力学的变化。果蝇边缘细胞提供了一个模型系统，在其中正向遗传学和活细胞成像相结合可以使研究人员在体内研究上皮细胞脱离和迁移的细胞及分子机制。
我们在筛选破坏边缘细胞迁移的突变时鉴定出了丝氨酸/苏氨酸激酶PAR-1（MARK/Kin1）的果蝇同源物。先前的研究鉴定出了两种蛋白质，Apontic和Notch，它们通过调节下游靶标的转录间接影响边缘细胞的脱离。相比之下，PAR-1直接调节边缘细胞和上皮细胞之间的顶-基极性以促进脱离。此外，PAR-1而非顶极性复合体蛋白PAR-3促进瞬时细胞突起的方向性，而边缘细胞需要这种方向性来感知趋化因子梯度。
我们得出结论，PAR-1依赖的顶-基极性是迁移的边缘细胞从相邻上皮细胞正确脱离所必需的。此外，由PAR-1控制的极性影响迁移细胞感知方向的能力，这是迁移的一个关键特征。因此，这项工作揭示了上皮细胞迁移两个不同但必不可少的步骤的新见解。
