The transcription factor NKX2-3 mediates p21 expression and ectodysplasin-A signaling in the enamel knot for cusp formation in tooth development
The transcription factor NKX2-3 mediates p21 expression and ectodysplasin-A signaling in the enamel knot for cusp formation in tooth development
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DOI：
10.1074/jbc.ra118.003373
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发表时间：
2018-09-21
影响因子：
4.8
通讯作者：
Fukumoto, Satoshi
中科院分区：
文献类型：
--
作者：
Han, Xue;Yoshizaki, Keigo;Fukumoto, Satoshi
牙齿形态发生是由外胚层和神经嵴来源的间充质之间的相互作用启动的。在牙齿发育过程中，牙尖通过精确控制细胞簇（称为釉质结）的增殖来调节，所述细胞簇存在于牙齿上皮细胞中。外胚层发育不良-A（EDA）与其受体EDAR的相互作用在这些釉质结的牙尖形成中起着关键作用，这些基因的突变是外胚层发育不良的原因。也有报道称，编码NK 2同源框转录因子家族成员的Nkx 2 -3的缺陷导致受影响牙齿的牙尖缺失。然而，NKX 2 -3在牙齿形态发生中的分子作用尚不清楚。利用小鼠胚胎基因芯片分析，我们发现Nkx 2 -3在牙齿发育过程中高度表达，并在牙齿形态发生过程中增加，特别是在牙尖形成过程中。我们还证明，NKX 2 -3是EDA的靶分子，对釉结中细胞周期调节因子p21的表达至关重要。此外，NKX 2 -3通过上调牙上皮中Bmp 2和Bmpr 2的表达水平来激活骨形态发生蛋白（BMP）信号通路，并降低牙上皮干细胞标志物SRY box 2（SOX 2）的表达。总之，我们的研究结果表明，EDA/NKX 2 -3信号是必不可少的牙釉质结形成在小鼠的牙齿形态发生。
Tooth morphogenesis is initiated by reciprocal interactions between the ectoderm and neural crest-derived mesenchyme. During tooth development, tooth cusps are regulated by precise control of proliferation of cell clusters, termed enamel knots, that are present among dental epithelial cells. The interaction of ectodysplasin-A (EDA) with its receptor, EDAR, plays a critical role in cusp formation by these enamel knots, and mutations of these genes is a cause of ectodermal dysplasia. It has also been reported that deficiency in Nkx2-3, encoding a member of the NK2 homeobox family of transcription factors, leads to cusp absence in affected teeth. However, the molecular role of NKX2-3 in tooth morphogenesis is not clearly understood. Using gene microarray analysis in mouse embryos, we found that Nkx2-3 is highly expressed during tooth development and increased during the tooth morphogenesis, especially during cusp formation. We also demonstrate that NKX2-3 is a target molecule of EDA and critical for expression of the cell cycle regulator p21 in the enamel knot. Moreover, NKX2-3 activated the bone morphogenetic protein (BMP) signaling pathway by up-regulating expression levels of Bmp2 and Bmpr2 in dental epithelium and decreased the expression of the dental epithelial stem cell marker SRY box 2 (SOX2). Together, our results indicate that EDA/NKX2-3 signaling is essential for enamel knot formation during tooth morphogenesis in mice.