Laminin α5 is required for dental epithelium growth and polarity and the development of tooth bud and shape
Laminin α5 is required for dental epithelium growth and polarity and the development of tooth bud and shape
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DOI：
10.1074/jbc.m509295200
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发表时间：
2006-02-24
影响因子：
4.8
通讯作者：
Yamada, Y
中科院分区：
文献类型：
--
作者：
Fukumoto, S;Miner, JH;Yamada, Y
在牙齿发育过程中，口腔外胚层和间充质通过基底膜协调相互作用，生长和分化，形成牙齿的适当形状和大小。含有层粘连蛋白 α 5 亚基的层粘连蛋白-10/11 (LM-511/521) 是牙胚基底膜中的主要层粘连蛋白。在这里，我们使用层粘连蛋白 α 5 缺失的小鼠原代牙上皮和牙胚器官培养物检查了层粘连蛋白 α 5 (Lama5) 在牙齿发育中的作用。 Lama5缺失小鼠会发育出牙尖形成有缺陷的小牙胚，并且牙上皮的增殖减少。此外，细胞极性和内牙上皮单层的形成也受到干扰。牙釉质结（牙胚发育的信号中心）有缺陷，牙上皮中的 Shh 和 Fgf4 表达显着减少。在缺乏层粘连蛋白 α 5 的情况下，内部牙上皮的基底膜变得不连续。在正常小鼠中，整合素α6β4（层粘连蛋白α5的受体）强烈定位于上皮的基底层，而在突变小鼠中，整合素α6β4在细胞表面周围表达。在原代牙上皮培养中，层粘连蛋白-10/11 促进细胞生长、扩散和丝状伪足样微刺形成。这种促进作用受到抗整合素 α 6 和 β 4 抗体、磷脂酰肌醇 3 激酶抑制剂和显性失活 Rho-GTP 家族蛋白 Cdc42 和 Rac 的抑制。在器官培养中，抗整合素 α 6 抗体和渥曼青霉素可减小牙胚的大小和形状。我们的研究表明，层粘连蛋白 α 5 是基底上皮细胞增殖和极性所必需的，并表明层粘连蛋白-10/11-整合素 α 6 β 4 和磷脂酰肌醇 3-激酶-Cdc42/Rac 通路之间的相互作用在确定牙胚的大小和形状方面发挥着重要作用。
In tooth development, the oral ectoderm and mesenchyme coordinately and reciprocally interact through the basement membrane for their growth and differentiation to form the proper shape and size of the tooth. Laminin alpha 5 subunit-containing laminin-10/11 ( LM-511/521) is the major laminin in the tooth germ basement membrane. Here, we have examined the role of laminin alpha 5 ( Lama5) in tooth development using laminin alpha 5-null mouse primary dental epithelium and tooth germ organ cultures. Lama5-null mice develop a small tooth germ with defective cusp formation and have reduced proliferation of dental epithelium. Also, cell polarity and formation of the monolayer of the inner dental epithelium are disturbed. The enamel knot, a signaling center for tooth germ development, is defective, and there is a significant reduction of Shh and Fgf4 expression in the dental epithelium. In the absence of laminin alpha 5, the basement membrane in the inner dental epithelium becomes discontinuous. In normal mice, integrin alpha 6 beta 4, a receptor for laminin alpha 5, is strongly localized at the basal layer of the epithelium, whereas in mutant mice, integrin alpha 6 beta 4 is expressed around the cell surface. In primary dental epithelium culture, laminin-10/11 promotes cell growth, spreading, and filopodia-like micro-spike formation. This promotion is inhibited by anti-integrin alpha 6 and beta 4 antibodies and by phosphatidylinositol 3-kinase inhibitors and dominant negative Rho-GTPase family proteins Cdc42 and Rac. In organ culture, anti-integrin alpha 6 antibody and wortmannin reduce tooth germ size and shape. Our studies demonstrate that laminin alpha 5 is required for the proliferation and polarity of basal epithelial cells and suggest that the interaction between laminin-10/11-integrin alpha 6 beta 4 and the phosphatidylinositol 3-kinase-Cdc42/Rac pathways play an important role in determining the size and shape of tooth germ.