A novel mutation of MSX1 in oligodontia inhibits odontogenesis of dental pulp stem cells via the ERK pathway.
A novel mutation of MSX1 in oligodontia inhibits odontogenesis of dental pulp stem cells via the ERK pathway.
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少牙症中 MSX1 的新突变通过 ERK 途径抑制牙髓干细胞的成牙
DOI：
10.1186/s13287-018-0965-3
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发表时间：
2018-08-22
影响因子：
7.5
通讯作者：
Zhou Y
中科院分区：
文献类型：
--
作者：
Xin T;Zhang T;Li Q;Yu T;Zhu Y;Yang R;Zhou Y
背景牙齿发育不全是最常见的发育异常之一，会影响患者的功能和美观。本研究的目的是寻找家族性牙齿发育的遗传线索并探讨其潜在机制，重点研究人牙髓干细胞（hDPSCs）在家族性牙齿发育中的作用。方法应用Sanger测序技术对一个中国家庭的少齿病病因进行分析。我们还对DPSCs进行了DNA转染和功能分析，以探索所鉴定的突变对这种表型的影响。结果在一个中国家庭中发现了一个新的移码突变，即MSX1外显子1上的20个核苷酸缺失（c.128_147del20, p.Met43Serfsx125），导致常染色体显性非综合征性少齿症。该突变与该家族的牙齿发育不全表型共分离。转染突变MSX1质粒的DPSCs与转染对照MSX1质粒的DPSCs相比，其成骨/成牙分化能力下降，牙本质唾液蛋白（DSPP）和骨唾液蛋白（BSP）表达水平降低。在机械上，对照MSX1表现出核定位，而突变MSX1则抑制其核易位并定位于细胞质上以抑制ERK磷酸化。此外，我们使用ERK抑制剂（U0126）处理msx1转染的对照DPSCs，抑制ERK通路，从而下调矿化结节的形成和牙源性基因的表达。结论发现一种新的MSX1突变可引起家族性非综合征性少牙症，并且MSX1通过ERK信号通路在人牙髓干细胞中机械地调控牙形成。
BackgroundTooth agenesis, one of the most common developmental anomalies, can affect the function and esthetics of patients. The aim of the present study was to identify genetic clues for familial tooth agenesis and explore the underlying mechanisms, focusing on the role of human dental pulp stem cells (hDPSCs).MethodsWe applied Sanger sequencing to identify the cause of oligodontia in a Chinese family. DNA transfection and functional analysis in DPSCs was also performed to explore the impact of the identified mutation on this phenotype.ResultsIn this study, a novel frameshift mutation, the twenty-nucleotide deletion (c.128_147del20, p.Met43Serfsx125), in exon1 of MSX1 was detected in a Chinese family causing autosomal dominant nonsyndromic oligodontia. The mutation cosegregated with the tooth agenesis phenotype in this family. DPSCs transfected with mutant MSX1 plasmid showed decreased capacity of osteo/odontogenic differentiation with a lower expression level of dentin sialophosphoprotein (DSPP) and bone sialoprotein (BSP) compared with those transfected with control MSX1 plasmid. Mechanically, control MSX1 showed nuclear localization while the mutant MSX1 inhibited its nuclear translocation and localized on the cytoplasm to inhibit ERK phosphorylation. Furthermore, we inhibited the ERK pathway using ERK inhibitor (U0126) treatment in control MSX1-transfected DPSCs which could downregulate mineralized nodule formation and the expression of odontogenic genes.ConclusionWe demonstrated a novel MSX1 mutation causing familial nonsyndromic oligodontia and mechanically MSX1 regulates odontogenesis through the ERK signaling pathway in human dental pulp stem cells.
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影响因子：
2
作者：
Bergendal, Birgitta;Klar, Joakim;Dahl, Niklas
通讯作者：
Dahl, Niklas
影响因子：
3
作者：
Mostowska, Adrianna;Biedziak, Barbara;Jagodzinski, Pawel P.
通讯作者：
Jagodzinski, Pawel P.
影响因子：
9.8
作者：
Lammi, L;Arte, S;Nieminen, P
通讯作者：
Nieminen, P
影响因子：
3.5
作者：
Tao, Ran;Jin, Buhe;He, Lin
通讯作者：
He, Lin
影响因子：
30.8
作者：
SATOKATA, I;MAAS, R
通讯作者：
MAAS, R