Breau Marie A, Dahmani Ahmed, Broders-Bondon Florence, Thiery Jean-Paul, Dufour Sylvie
UMR144, CNRS-Institut Curie, Paris cedex 05, France.
Development. 2009 Aug;136(16):2791-801. doi: 10.1242/dev.031419.
Integrins are the major adhesive receptors for extracellular matrix and have various roles in development. To determine their role in cell migration, the gene encoding the beta1 integrin subunit (Itgb1) was conditionally deleted in mouse neural crest cells just after their emigration from the neural tube. We previously identified a major defect in gut colonisation by conditional Itgb1-null enteric neural crest cells (ENCCs) resulting from their impaired migratory abilities and enhanced aggregation properties. Here, we show that the migration defect occurs primarily during the invasion of the caecum, when Itgb1-null ENCCs stop their normal progression before invading the caecum and proximal hindgut by becoming abnormally aggregated. We found that the caecum and proximal hindgut express high levels of fibronectin and tenascin-C, two well-known ligands of integrins. In vitro, tenascin-C and fibronectin have opposite effects on ENCCs, with tenascin-C decreasing migration and adhesion and fibronectin strongly promoting them. Itgb1-null ENCCs exhibited an enhanced response to the inhibitory effect of tenascin-C, whereas they were insensitive to the stimulatory effect of fibronectin. These findings suggest that beta1 integrins are required to overcome the tenascin-C-mediated inhibition of migration within the caecum and proximal hindgut and to enhance fibronectin-dependent migration in these regions.
整合素是细胞外基质的主要黏附受体，在发育过程中发挥着多种作用。为了确定它们在细胞迁移中的作用，编码β1整合素亚基（Itgb1）的基因在小鼠神经嵴细胞刚从神经管迁出后被条件性敲除。我们之前发现，条件性Itgb1基因缺失的肠神经嵴细胞（ENCCs）在肠道定植方面存在主要缺陷，这是由于它们的迁移能力受损和聚集特性增强所致。在这里，我们表明迁移缺陷主要发生在盲肠侵袭期间，此时Itgb1基因缺失的ENCCs在侵袭盲肠和近端后肠之前停止正常进展，因为它们异常聚集。我们发现盲肠和近端后肠表达高水平的纤连蛋白和腱生蛋白-C，这两种都是整合素的著名配体。在体外，腱生蛋白-C和纤连蛋白对ENCCs有相反的作用，腱生蛋白-C降低迁移和黏附，而纤连蛋白强烈促进迁移和黏附。Itgb1基因缺失的ENCCs对腱生蛋白-C的抑制作用表现出增强的反应，而它们对纤连蛋白的刺激作用不敏感。这些发现表明，β1整合素是克服腱生蛋白-C介导的对盲肠和近端后肠内迁移的抑制以及增强这些区域中纤连蛋白依赖性迁移所必需的。
