Fibronectin requirement in branching morphogenesis
Fibronectin requirement in branching morphogenesis
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DOI：
10.1038/nature01712
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发表时间：
2003-06-19
期刊：
影响因子：
64.8
通讯作者：
Yamada, KM
中科院分区：
文献类型：
--
作者：
Sakai, T;Larsen, M;Yamada, KM
许多器官，包括唾液腺、肺和肾，在胚胎发育期间通过上皮分支形成。在分支形态发生中，重复的上皮裂缝和芽的形成产生了许多器官特有的复杂的三维分支结构（1-3）。虽然机制知之甚少，但可能涉及某些调节蛋白的位点特异性积累。在这里，我们表明，细胞外基质蛋白纤连蛋白（4，5）是必不可少的裂缝形成过程中开始上皮分支。纤维连接蛋白信使RNA和原纤维出现短暂的和局灶性的形成下颌下腺上皮细胞的裂缝区域，伴随着相邻的钙粘蛋白定位的损失。通过使用小干扰RNA和抗纤连蛋白或抗整联蛋白抗体的抑制降低纤连蛋白浓度阻断裂缝形成和分支。外源性纤连蛋白促进裂隙形成和分枝。在发育中的肺和肾中观察到纤连蛋白抑制和增强的类似作用。机制研究表明，纤维状纤连蛋白可以诱导培养的人唾液腺上皮细胞的细胞-基质粘附与细胞连接处的钙粘蛋白的局部损失。因此，纤连蛋白的表达是必要的裂缝形成分支形态发生与细胞-细胞粘附细胞-基质粘附的转换。
Many organs, including salivary glands, lung and kidney, are formed during embryonic development by epithelial branching. In branching morphogenesis, repetitive epithelial cleft and bud formation create the complex three-dimensional branching structures characteristic of many organs(1-3). Although the mechanisms are poorly understood, one might involve the site-specific accumulation of some regulatory protein. Here we show that the extracellular matrix protein fibronectin(4,5) is essential for cleft formation during the initiation of epithelial branching. Fibronectin messenger RNA and fibrils appeared transiently and focally in forming cleft regions of submandibular salivary-gland epithelia, accompanied by an adjacent loss of cadherin localization. Decreasing the fibronectin concentration by using small interfering RNA and inhibition by anti-fibronectin or anti-integrin antibodies blocked cleft formation and branching. Exogenous fibronectin accelerated cleft formation and branching. Similar effects of fibronectin suppression and augmentation were observed in developing lung and kidney. Mechanistic studies revealed that fibrillar fibronectin can induce cell-matrix adhesions on cultured human salivary epithelial cells with a local loss of cadherins at cell-cell junctions. Thus, fibronectin expression is required for cleft formation in branching morphogenesis associated with the conversion of cell-cell adhesions to cell-matrix adhesions.