Before the secretion of hard dental tissues, tooth germs undergo several distinctive stages of development (dental lamina, bud, cap and bell). Every stage is characterized by specific proliferation patterns, which is regulated by various morphogens, growth factors and homeodomain proteins. The role of MSX homeodomain proteins in odontogenesis is rather complex. Expression domains of genes encoding for murine Msx1/2 during development are observed in tissues containing highly proliferative progenitor cells. Arrest of tooth development in Msx knockout mice can be attributed to impaired proliferation of progenitor cells. In Msx1 knockout mice, these progenitor cells start to differentiate prematurely as they strongly express cyclin-dependent kinase inhibitor p19^INK4d. p19^INK4d induces terminal differentiation of cells by blocking the cell cycle in mitogen-responsive G1 phase. Direct suppression of p19^INK4d by Msx1 protein is, therefore, important for maintaining proliferation of progenitor cells at levels required for the normal progression of tooth development. In this study, we examined the expression patterns of MSX1, MSX2 and p19^INK4d in human incisor tooth germs during the bud, cap and early bell stages of development. The distribution of expression domains of p19^INK4d throughout the investigated period indicates that p19^INK4d plays active role during human tooth development. Furthermore, comparison of expression domains of p19^INK4d with those of MSX1, MSX2 and proliferation markers Ki67, Cyclin A2 and pRb, indicates that MSX-mediated regulation of proliferation in human tooth germs might not be executed by the mechanism similar to one described in developing tooth germs of wild-type mouse.

在分泌坚硬的牙齿组织之前，牙胚经历了几个不同的发育阶段（牙齿椎板，芽，帽和钟形）。每个阶段都以特定的增殖模式为特征，该增殖模式受各种形态发生素，生长因子和同源结构域蛋白的调节。MSX同源域蛋白在牙生成中的作用相当复杂。在含有高度增殖祖细胞的组织中观察到发育期间编码鼠Msx1 / 2的基因的表达域。Msx基因敲除小鼠的牙齿发育停滞可归因于祖细胞增殖受损。在Msx1基因敲除小鼠中，这些祖细胞开始过早分化，因为它们强烈表达细胞周期蛋白依赖性激酶抑制剂p19 ^INK4d。p19 ^INK4d通过阻断有丝分裂应答性G1期的细胞周期来诱导细胞的终末分化。因此，Msx1蛋白直接抑制p19 ^INK4d对于维持祖细胞正常牙齿发育所需水平的祖细胞增殖至关重要。在这项研究中，我们检查了在发育的芽，帽和早期钟形过程中，人类门齿牙胚中MSX1，MSX2和p19 ^INK4d的表达模式。P19的表达域的分布^INK4d在整个调查期间表示P19 ^INK4d扮演人类牙齿发育过程中发挥积极作用。此外，p19 ^INK4d表达域的比较 与MSX1，MSX2以及增殖标志物Ki67，Cyclin A2和pRb一起使用，表明MSX介导的人类牙胚增殖调控可能无法通过与野生型小鼠牙胚发育过程中描述的类似机制进行。