Dassule H R, Lewis P, Bei M, Maas R, McMahon A P
Department of Molecular and Cellular Biology, The Biolabs, Divinity Avenue, Cambridge, MA 02138, USA.
Development. 2000 Nov;127(22):4775-85. doi: 10.1242/dev.127.22.4775.
During mammalian tooth development, the oral ectoderm and mesenchyme coordinate their growth and differentiation to give rise to organs with precise shapes, sizes and functions. The initial ingrowth of the dental epithelium and its associated dental mesenchyme gives rise to the tooth bud. Next, the epithelial component folds to give the tooth its shape. Coincident with this process, adjacent epithelial and mesenchymal cells differentiate into enamel-secreting ameloblasts and dentin-secreting odontoblasts, respectively. Growth, morphogenesis and differentiation of the epithelium and mesenchyme are coordinated by secreted signaling proteins. Sonic hedgehog (Shh) encodes a signaling peptide which is present in the oral epithelium prior to invagination and in the tooth epithelium throughout its development. We have addressed the role of Shh in the developing tooth in mouse by using a conditional allele to remove Shh activity shortly after ingrowth of the dental epithelium. Reduction and then loss of Shh function results in a cap stage tooth rudiment in which the morphology is severely disrupted. The overall size of the tooth is reduced and both the lingual epithelial invagination and the dental cord are absent. However, the enamel knot, a putative organizer of crown formation, is present and expresses Fgf4, Wnt10b, Bmp2 and Lef1, as in the wild type. At birth, the size and the shape of the teeth are severely affected and the polarity and organization of the ameloblast and odontoblast layers is disrupted. However, both dentin- and enamel-specific markers are expressed and a large amount of tooth-specific extracellular matrix is produced. This observation was confirmed by grafting studies in which tooth rudiments were cultured for several days under kidney capsules. Under these conditions, both enamel and dentin were deposited even though the enamel and dentin layers remained disorganized. These studies demonstrate that Shh regulates growth and determines the shape of the tooth. However, Shh signaling is not essential for differentiation of ameloblasts or odontoblasts.
在哺乳动物牙齿发育过程中，口腔外胚层和间充质协调它们的生长与分化，从而形成具有精确形状、大小和功能的器官。牙上皮及其相关牙间充质的最初向内生长形成牙蕾。接下来，上皮成分折叠赋予牙齿形状。与此过程同时发生的是，相邻的上皮细胞和间充质细胞分别分化为分泌釉质的成釉细胞和分泌牙本质的成牙本质细胞。上皮和间充质的生长、形态发生及分化由分泌的信号蛋白协调。音猬因子（Shh）编码一种信号肽，在向内生长之前它存在于口腔上皮中，并且在牙齿上皮发育的整个过程中都存在。我们通过使用条件等位基因在牙上皮向内生长后不久去除Shh活性，来研究Shh在小鼠发育牙齿中的作用。Shh功能的降低继而丧失导致帽状期牙胚，其形态严重紊乱。牙齿的整体大小减小，舌侧上皮内陷和牙索均不存在。然而，釉结（一种假定的牙冠形成组织者）存在，并且如在野生型中一样表达Fgf4、Wnt10b、Bmp2和Lef1。出生时，牙齿的大小和形状受到严重影响，成釉细胞层和成牙本质细胞层的极性及组织结构被破坏。然而，牙本质和釉质特异性标志物均有表达，并且产生了大量牙齿特异性细胞外基质。通过移植研究证实了这一观察结果，在移植研究中，牙胚在肾被膜下培养数天。在这些条件下，即使釉质层和牙本质层仍然无序，但仍有釉质和牙本质沉积。这些研究表明，Shh调节生长并决定牙齿的形状。然而，Shh信号传导对于成釉细胞或成牙本质细胞的分化并非必不可少。
