Section of Molecular Cell and Developmental Biology and Institute for Cell and Molecular Biology, University of Texas at Austin, Austin, TX 78722, USA.
Mol Biol Cell. 2012 Dec;23(24):4725-38. doi: 10.1091/mbc.E12-09-0672. Epub 2012 Oct 24.
Lens fiber formation and morphogenesis requires a precise orchestration of cell- extracellular matrix (ECM) and cell-cell adhesive changes in order for a lens epithelial cell to adopt a lens fiber fate, morphology, and migratory ability. The cell-ECM interactions that mediate these processes are largely unknown, and here we demonstrate that fibronectin1 (Fn1), an ECM component, and integrin α5, its cellular binding partner, are required in the zebrafish lens for fiber morphogenesis. Mutations compromising either of these proteins lead to cataracts, characterized by defects in fiber adhesion, elongation, and packing. Loss of integrin α5/Fn1 does not affect the fate or viability of lens epithelial cells, nor does it affect the expression of differentiation markers expressed in lens fibers, although nucleus degradation is compromised. Analysis of the intracellular mediators of integrin α5/Fn1 activity focal adhesion kinase (FAK) and integrin-linked kinase (ILK) reveals that FAK, but not ILK, is also required for lens fiber morphogenesis. These results support a model in which lens fiber cells use integrin α5 to migrate along a Fn-containing substrate on the apical side of the lens epithelium and on the posterior lens capsule, likely activating an intracellular signaling cascade mediated by FAK in order to orchestrate the cytoskeletal changes in lens fibers that facilitate elongation, migration, and compaction.
晶状体纤维的形成和形态发生需要精细地协调细胞-细胞外基质（ECM）和细胞-细胞黏附的变化，以使晶状体上皮细胞获得晶状体纤维命运、形态和迁移能力。介导这些过程的细胞-ECM 相互作用在很大程度上是未知的，在这里我们证明纤维连接蛋白 1（Fn1），一种 ECM 成分，及其细胞结合伴侣整合素 α5，在斑马鱼晶状体中对于纤维形态发生是必需的。这些蛋白质中的任何一种发生突变都会导致白内障，其特征是纤维黏附、伸长和排列缺陷。整合素 α5/Fn1 的缺失既不影响晶状体上皮细胞的命运或活力，也不影响晶状体纤维中表达的分化标志物的表达，尽管核降解受到损害。对整合素 α5/Fn1 活性的细胞内介质粘着斑激酶（FAK）和整合素连接激酶（ILK）的分析表明，FAK 而不是 ILK，对于晶状体纤维形态发生也是必需的。这些结果支持这样一种模型，即晶状体纤维细胞使用整合素 α5 沿着晶状体上皮细胞的顶端和后晶状体囊上富含 Fn 的底物迁移，可能激活由 FAK 介导的细胞内信号级联，以协调促进伸长、迁移和压缩的晶状体纤维中的细胞骨架变化。
