Nephronectin plays critical roles in Sox2 expression and proliferation in dental epithelial stem cells via EGF-like repeat domains.
Nephronectin plays critical roles in Sox2 expression and proliferation in dental epithelial stem cells via EGF-like repeat domains.
复制标题
DOI：
10.1038/srep45181
复制
发表时间：
2017-03-27
影响因子：
4.6
通讯作者：
Fukumoto S
中科院分区：
文献类型：
--
作者：
Arai C;Yoshizaki K;Miyazaki K;Saito K;Yamada A;Han X;Funada K;Fukumoto E;Haruyama N;Iwamoto T;Takahashi I;Fukumoto S
牙齿发育是由上皮-间充质相互作用通过基底膜（BM）和生长因子启动的。在本研究中，我们发现，肾连蛋白（Npnt），BM的一个组成部分，是高度表达在发育中的牙齿。Npnt定位于牙胚颊侧的BM中，并显示与牙上皮干细胞标记物Sox 2相反的表达模式。为了确定Npnt在牙齿发育过程中的作用，我们使用离体器官和牙齿上皮细胞培养物进行了敲低和过表达实验。我们的研究结果表明，Npnt的损失诱导异位Sox 2阳性细胞和减少牙胚大小。Npnt的过度表达显示牙上皮细胞增殖增加，而Sox 2阳性细胞的数量减少。Npnt含有5个EGF样重复结构域，以及一个RGD序列和MAM结构域。我们发现EGF样重复序列对Sox 2表达和细胞增殖至关重要。此外，Npnt通过EGF样重复结构域激活EGF受体（EGFR）并诱导PI 3 K-Akt信号通路。我们的研究结果表明，Npnt在牙齿上皮干细胞分化和增殖中起着关键的支架作用，并在牙齿发育过程中调节Sox 2的表达。
Tooth development is initiated by epithelial-mesenchymal interactions via basement membrane (BM) and growth factors. In the present study, we found that nephronectin (Npnt), a component of the BM, is highly expressed in the developing tooth. Npnt localizes in the BM on the buccal side of the tooth germ and shows an expression pattern opposite that of the dental epithelial stem cell marker Sox2. To identify the roles of Npnt during tooth development, we performed knockdown and overexpression experiments using ex vivo organ and dental epithelial cell cultures. Our findings showed that loss of Npnt induced ectopic Sox2-positive cells and reduced tooth germ size. Over expression of Npnt showed increased proliferation, whereas the number of Sox2-positive cells was decreased in dental epithelial cells. Npnt contains 5 EGF-like repeat domains, as well as an RGD sequence and MAM domain. We found that the EGF-like repeats are critical for Sox2 expression and cell proliferation. Furthermore, Npnt activated the EGF receptor (EGFR) via the EGF-like repeat domains and induced the PI3K-Akt signaling pathway. Our results indicate that Npnt plays a critical scaffold role in dental epithelial stem cell differentiation and proliferation, and regulates Sox2 expression during tooth development.