The life history of an embryonic signaling center: BMP-4 induces p21 and is associated with apoptosis in the mouse tooth enamel knot.
The life history of an embryonic signaling center: BMP-4 induces p21 and is associated with apoptosis in the mouse tooth enamel knot.
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发表时间：
1998-01
期刊：
影响因子：
4.6
通讯作者：
J. Jernvall;T. Åberg;P. Kettunen;S. Keränen;Irma Thesleff
中科院分区：
文献类型：
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作者：
J. Jernvall;T. Åberg;P. Kettunen;S. Keränen;Irma Thesleff
釉质结是哺乳动物牙齿发育初期的一种上皮结构。到目前为止，导致釉质结形成和消失的形态学、细胞和分子事件尚未被描述。在这里，我们报告说，细胞增殖的停止在釉结在小鼠磨牙与细胞周期蛋白依赖性激酶抑制剂p21的表达。我们发现，p21的表达诱导骨形态发生蛋白4（BMP-4）在离体牙上皮细胞。由于BMP-4仅在釉质结形成开始时在底层牙间充质中表达，这些结果支持细胞周期蛋白依赖性激酶抑制剂作为上皮-间充质相互作用中的诱导细胞分化因子的作用。此外，我们表明，p21的表达在釉结中的BMP-4的表达，随后由分化的釉结细胞凋亡。原位杂交和Tunel染色后连续切片的三维重建表明BMP-4转录和凋亡细胞的确切共分布。BMP-4在离体牙上皮细胞中刺激细胞凋亡，但仅在三分之一的外植体中。我们的结论是，BMP-4可能参与诱导的上皮釉结，上皮细胞周期蛋白依赖性激酶抑制剂的间质诱导剂，并在终止釉结信号功能，通过参与调节程序性细胞死亡。这些结果表明，釉结的生活史是密切相关的牙齿形状的发展和支持的启动釉结作为胚胎信号中心的作用。
The enamel knot, a transient epithelial structure, appears at the onset of mammalian tooth shape development. Until now, the morphological, cellular and molecular events leading to the formation and disappearance of the enamel knot have not been described. Here we report that the cessation of cell proliferation in the enamel knot in mouse molar teeth is linked with the expression of the cyclin-dependent kinase inhibitor p21. We show that p21 expression is induced by bone morphogenetic protein 4 (BMP-4) in isolated dental epithelia. As Bmp-4 is expressed only in the underlying dental mesenchyme at the onset of the enamel knot formation, these results support the role of the cyclin-dependent kinase inhibitors as inducible cell differentiation factors in epithelial-mesenchymal interactions. Furthermore, we show that the expression of p21 in the enamel knot is followed by Bmp-4 expression, and subsequently by apoptosis of the differentiated enamel knot cells. Three-dimensional reconstructions of serial sections after in situ hybridization and Tunel-staining indicated an exact codistribution of Bmp-4 transcripts and apoptotic cells. Apoptosis was stimulated by BMP-4 in isolated dental epithelia, but only in one third of the explants. We conclude that Bmp-4 may be involved both in the induction of the epithelial enamel knot, as a mesenchymal inducer of epithelial cyclin-dependent kinase inhibitors, and later in the termination of the enamel knot signaling functions by participating in the regulation of programmed cell death. These results show that the life history of the enamel knot is intimately linked to the initiation of tooth shape development and support the role of the enamel knot as an embryonic signaling center.