BMPs and FGFs target Notch signalling via jagged 2 to regulate tooth morphogenesis and cytodifferentiation
BMPs and FGFs target Notch signalling via jagged 2 to regulate tooth morphogenesis and cytodifferentiation
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DOI：
10.1242/dev.049528
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发表时间：
2010-09-15
期刊：
影响因子：
4.6
通讯作者：
Bluteau, Gilles
中科院分区：
文献类型：
--
作者：
Mitsiadis, Thimios A.;Graf, Daniel;Bluteau, Gilles
Notch信号通路是一种进化保守的细胞间信号传导机制，对细胞命运规范和胚胎正常发育至关重要。我们分析了锯齿2 （Jag2）基因的表达、调控和功能，该基因编码Notch受体家族的配体，在发育小鼠牙齿中。Jag2在上皮细胞中表达，产生牙釉质的成釉细胞来自牙齿发育的早期阶段。组织重组实验表明，其在上皮中的表达受间质来源信号的调控。在体外培养的牙体中，局部应用成纤维细胞生长因子上调Jag2的表达，而骨形态发生蛋白则引起相反的效果。Jag2 notch相互作用结构域缺失的纯合小鼠出现各种严重的牙齿异常。在磨牙中，牙冠形态畸形，形成额外的尖牙。这是由于釉质结（一种参与臼齿冠形态发生的上皮信号结构）的改变，其中Bmp4的表达和凋亡发生了改变。门牙细胞分化和牙釉质基质沉积受到抑制。Tbx1是成釉细胞分化和牙釉质形成的标志，在Jag2（-/-）牙中表达显著降低。综上所述，这些结果表明由Jag2介导的Notch信号对于正常牙齿发育是不可或缺的。
The Notch signalling pathway is an evolutionarily conserved intercellular signalling mechanism that is essential for cell fate specification and proper embryonic development. We have analysed the expression, regulation and function of the jagged 2 (Jag2) gene, which encodes a ligand for the Notch family of receptors, in developing mouse teeth. Jag2 is expressed in epithelial cells that give rise to the enamel-producing ameloblasts from the earliest stages of tooth development. Tissue recombination experiments showed that its expression in epithelium is regulated by mesenchyme-derived signals. In dental explants cultured in vitro, the local application of fibroblast growth factors upregulated Jag2 expression, whereas bone morphogenetic proteins provoked the opposite effect. Mice homozygous for a deletion in the Notch-interaction domain of Jag2 presented a variety of severe dental abnormalities. In molars, the crown morphology was misshapen, with additional cusps being formed. This was due to alterations in the enamel knot, an epithelial signalling structure involved in molar crown morphogenesis, in which Bmp4 expression and apoptosis were altered. In incisors, cytodifferentiation and enamel matrix deposition were inhibited. The expression of Tbx1 in ameloblast progenitors, which is a hallmark for ameloblast differentiation and enamel formation, was dramatically reduced in Jag2(-/-) teeth. Together, these results demonstrate that Notch signalling mediated by Jag2 is indispensable for normal tooth development.