Integrin α5/fibronectin1 and focal adhesion kinase are required for lens fiber morphogenesis in zebrafish.
Integrin α5/fibronectin1 and focal adhesion kinase are required for lens fiber morphogenesis in zebrafish.
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DOI：
10.1091/mbc.e12-09-0672
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发表时间：
2012-12
影响因子：
3.3
通讯作者：
Gross JM
中科院分区：
文献类型：
--
作者：
Hayes JM;Hartsock A;Clark BS;Napier HR;Link BA;Gross JM
Fn 1和Itga 5中的斑马鱼突变体具有白内障，其特征在于纤维粘附、伸长和包装的缺陷。对整合素α5/Fn 1活性的细胞内介质FAK和ILK的分析表明，FAK而不是ILK也是透镜纤维形态发生所必需的，并且在透镜纤维形态发生过程中它自主地起细胞作用。透镜纤维形成和形态发生需要细胞-细胞外基质（ECM）和细胞-细胞粘附变化的精确协调，以使透镜上皮细胞采用透镜纤维命运、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，纤连蛋白1（Fn 1），ECM组件，和整合素α5，其细胞结合伴侣，需要在斑马鱼透镜纤维形态发生。损害这些蛋白质的突变导致白内障，其特征在于纤维粘附，伸长和包装的缺陷。整合素α5/Fn 1的缺失不影响透镜上皮细胞的命运或活力，也不影响透镜纤维中表达的分化标记物的表达，尽管细胞核降解受损。对整合素α5/Fn 1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也是透镜纤维形态发生所必需的。这些结果支持了一个模型，其中透镜纤维细胞使用整合素α5沿着透镜上皮细胞顶侧和后透镜囊上的含Fn基质迁移，可能激活由FAK介导的细胞内信号级联，以协调透镜纤维中的细胞骨架变化，促进伸长、迁移和压实。
Zebrafish mutants in Fn1 and Itga5 possess cataracts, characterized by defects in fiber adhesion, elongation, and packing. Analysis of the intracellular mediators of integrin α5/Fn1 activity FAK and ILK reveals that FAK, but not ILK, is also required for lens fiber morphogenesis and that it acts cell autonomously during lens fiber morphogenesis. 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.