PDF(Pubmed)
Abstract：
Collective cell migration is fundamental for the development of organisms and in the adult for tissue regeneration and in pathological conditions such as cancer. Migration as a coherent group requires the maintenance of cell-cell interactions, while contact inhibition of locomotion (CIL), a local repulsive force, can propel the group forward. Here we show that the cell-cell interaction molecule, N-cadherin, regulates both adhesion and repulsion processes during Schwann cell (SC) collective migration, which is required for peripheral nerve regeneration. However, distinct from its role in cell-cell adhesion, the repulsion process is independent of N-cadherin trans-homodimerisation and the associated adherens junction complex. Rather, the extracellular domain of N-cadherin is required to present the repulsive Slit2/Slit3 signal at the cell surface. Inhibiting Slit2/Slit3 signalling inhibits CIL and subsequently collective SC migration, resulting in adherent, nonmigratory cell clusters. Moreover, analysis of ex vivo explants from mice following sciatic nerve injury showed that inhibition of Slit2 decreased SC collective migration and increased clustering of SCs within the nerve bridge. These findings provide insight into how opposing signals can mediate collective cell migration and how CIL pathways are promising targets for inhibiting pathological cell migration.
摘要：
集体细胞迁移是生物体和成虫发育的基础,用于组织再生和病理状况，如癌症。作为一个连贯的群体，迁移需要维持细胞间的相互作用，而运动接触抑制(CIL)，局部斥力,可以推动团队前进。这里我们展示了细胞-细胞相互作用分子，N-钙黏着蛋白,调节大鼠雪旺细胞（SC）集体迁移过程中的粘附和排斥过程，这是周围神经再生所必需的。然而,与其在细胞-细胞粘附中的作用不同，排斥过程与N-钙黏着蛋白的反式同二聚化和相关的粘附连接复合物无关。相反，需要N-钙粘蛋白的胞外结构域以在细胞表面呈现排斥性Slit2/Slit3信号。抑制Slit2/Slit3信号抑制CIL并随后集体施万细胞迁移，导致粘附，非迁移细胞簇。此外，对坐骨神经损伤后小鼠离体外植体的分析表明，抑制Slit2可降低雪旺氏细胞的集体迁移，并增加神经桥内雪旺氏细胞的聚集。这些发现提供了有关相反信号如何介导集体细胞迁移的见解，以及hhCIL途径如何成为抑制病理性细胞迁移的有希望的靶标。
