Komura Hitomi, Ogita Hisakazu, Ikeda Wataru, Mizoguchi Akira, Miyoshi Jun, Takai Yoshimi
Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita, Osaka 565-0871, Japan.
Genes Cells. 2008 Jan;13(1):79-90. doi: 10.1111/j.1365-2443.2007.01150.x.
Afadin directly links nectin, an immunoglobulin-like cell-cell adhesion molecule, to actin filaments (F-actin) at adherens junctions (AJs). The nectin-afadin complex is important for the formation of not only AJs but also tight junctions (TJs) in epithelial cells. Studies using afadin-knockout mice have revealed that afadin is indispensable for embryonic development by organizing the formation of cell-cell junctions. However, the molecular mechanism of cell-cell junction disorganization during embryonic development in afadin-knockout mice is poorly understood. To address this, we took advantage of embryoid bodies (EBs) as a model system. The formation of cell-cell junctions including AJs and TJs was impaired in afadin-null EBs. The proper accumulation of the Par complex and the activation of Cdc42 and atypical PKC (aPKC), which are crucial for the formation of cell polarity, were also inhibited by knockout of afadin. In addition, the disruption of afadin caused the abnormal deposition of laminin and the dislocalization of its receptors integrin alpha(6) and integrin beta(1). These results indicate that afadin organizes the formation of cell-cell junctions by regulating cell polarization in early embryonic development.
Afadin可将免疫球蛋白样细胞间黏附分子nectin直接与黏附连接（AJs）处的肌动蛋白丝（F-肌动蛋白）相连。nectin-afadin复合物不仅对上皮细胞中AJs的形成很重要，对紧密连接（TJs）的形成也很重要。使用afadin基因敲除小鼠的研究表明，afadin通过组织细胞间连接的形成对胚胎发育不可或缺。然而，afadin基因敲除小鼠胚胎发育过程中细胞间连接紊乱的分子机制尚不清楚。为了解决这个问题，我们利用胚状体（EBs）作为模型系统。在afadin基因缺失的EBs中，包括AJs和TJs在内的细胞间连接的形成受到损害。afadin基因敲除还抑制了对细胞极性形成至关重要的Par复合物的正常积累以及Cdc42和非典型蛋白激酶C（aPKC）的激活。此外，afadin的破坏导致层粘连蛋白异常沉积及其受体整合素α(6)和整合素β(1)的错位。这些结果表明，afadin在早期胚胎发育中通过调节细胞极性来组织细胞间连接的形成。
