PDF(Pubmed)
Abstract：
BMP2 signaling plays a pivotal role in odontoblast differentiation and maturation during odontogenesis. Teeth lacking Bmp2 exhibit a morphology reminiscent of dentinogenesis imperfecta (DGI), associated with mutations in dentin matrix protein 1 (DMP1) and dentin sialophosphoprotein (DSPP) genes. Mechanisms by which BMP2 signaling influences expressions of DSPP and DMP1 and contributes to DGI remain elusive. To study the roles of BMP2 in dentin development, we generated Bmp2 conditional knockout (cKO) mice. Through a comprehensive approach involving RNA-seq, immunohistochemistry, promoter activity, ChIP, and Re-ChIP, we investigated downstream targets of Bmp2. Notably, the absence of Bmp2 in cKO mice led to dentin insufficiency akin to DGI. Disrupted Bmp2 signaling was linked to decreased expression of Dspp and Dmp1, as well as alterations in intracellular translocation of transcription factors Dlx3 and Sp7. Intriguingly, upregulation of Dlx3, Dmp1, Dspp, and Sp7, driven by BMP2, fostered differentiation of dental mesenchymal cells and biomineralization. Mechanistically, BMP2 induced phosphorylation of Dlx3, Sp7, and histone acetyltransferase GCN5 at Thr and Tyr residues, mediated by Akt and Erk42/44 kinases. This phosphorylation facilitated protein nuclear translocation, promoting interactions between Sp7 and Dlx3, as well as with GCN5 on Dspp and Dmp1 promoters. The synergy between Dlx3 and Sp7 bolstered transcription of Dspp and Dmp1. Notably, BMP2-driven GCN5 acetylated Sp7 and histone H3, while also recruiting RNA polymerase II to Dmp1 and Dspp chromatins, enhancing their transcriptions. Intriguingly, BMP2 suppressed the expression of histone deacetylases. we unveil hitherto uncharted involvement of BMP2 in dental cell differentiation and dentine development through pAkt/pErk42/44/Dlx3/Sp7/GCN5/Dspp/Dmp1.
摘要：
BMP2信号在成牙本质分化和成熟过程中起关键作用。缺乏Bmp2的牙齿表现出让人联想到牙本质发育不全（DGI）的形态，与牙本质基质蛋白1（DMP1）和牙本质唾液酸糖蛋白（DSPP）基因突变相关。BMP2信号传导影响DSPP和DMP1表达并有助于DGI的机制仍然难以捉摸。研究BMP2在牙本质发育中的作用,我们产生了Bmp2条件性敲除(cKO)小鼠。通过涉及RNA-seq的综合方法，免疫组织化学，启动子活性，ChIP,和Re-ChIP,我们调查了Bmp2的下游目标。值得注意的是,cKO小鼠中Bmp2的缺失导致类似于DGI的牙本质功能不全。Bmp2信号传导中断与Dspp和Dmp1的表达减少以及转录因子Dlx3和Sp7的细胞内易位改变有关。有趣的是，Dlx3，Dmp1，Dspp的上调，由BMP2驱动的Sp7促进了牙间充质细胞的分化和生物矿化。机械上,BMP2在Thr和Tyr残基处诱导Dlx3，Sp7和组蛋白乙酰转移酶GCN5的磷酸化，由Akt和Erk42/44激酶介导。这种磷酸化促进了蛋白质核易位，促进Sp7和Dlx3之间的相互作用，以及与GCN5在Dspp和Dmp1启动子上的相互作用。Dlx3和Sp7之间的协同作用支持Dspp和Dmp1的转录。值得注意的是,BMP2驱动的GCN5乙酰化Sp7和组蛋白H3，同时也招募RNA聚合酶II到Dmp1和Dspp色谱，增强他们的转录。有趣的是，BMP2抑制组蛋白脱乙酰酶的表达。我们通过pAkt/pErk42/44/Dlx3/Sp7/GCN5/Dspp/Dmp1揭示了迄今为止BMP2在牙齿细胞分化和牙本质发育中的未知参与。
