CD133和Notch对牙上皮细胞增殖分化的交互调节作用研究

The Notch signaling is an evolutionarily conserved pathway that regulates cell-cell communication and cell fate. CD133 is often expressed by stem cells but its functions are still unknown. Increasing evidence suggest Notch and CD133 might have close biological connection. Based on much preliminary results, the hypothesis has been put forward that Notch and CD133 play synergistic roles in regulating epithelial cell fates. Using the tooth as a model system, we find that Notch1 and CD133 are co-expressed in the epithelium of the developing tooth. Notch1 and CD133 also co-localize in oral mucosa epithelial cells, suggesting a possible common functional link between these two molecules. The significance of these findings is reflected by the further results that CD133 knock-out mice exhibit a defective tooth epithelial developmental phenotype (i.e., amelogenesis imperfecta) similar to that observed in mutant mice in which canonical Notch signaling is conditionally inhibited. This phenotype is at least partially due to decreased epithelial stem cell numbers and the defective terminal lineage differentiation. Moreover, in cultured tooth epithelial cells, we observed (i) that increased CD133 expression induces stem cell marker expression and lineage differentiation in a Notch/RBP-Jk-dependent manner and (ii) that increased Notch activity elicits effects similar to those of CD133 overexpression. In this project, we plan to further develop this line of work with a systematic investigation of the combined role of Notch and CD133 signaling in regulating epithelial cell fate. This work is of potential high impact for other systems in which Notch and CD133 pathways are involved in the control of cell fate determination and plasticity.

Notch信号通路是细胞间相互作用以控制细胞命运的一种重要方式。CD133近年来作为多种干细胞的表面标志而被重视，但目前与CD133相互作用的分子及其在干细胞分化中的功能仍不清楚。许多证据表明CD133和Notch信号之间可能有功能上的联系。本课题以牙齿作为模型，根据大量的前期研究工作结果提出假设：CD133与Notch信号在牙上皮细胞的增殖分化过程中有交互调控作用，可影响成釉细胞的发育及牙釉质的形成。课题以小鼠切牙为研究对象，从CD133和Notch在釉质发育中的表达，到两者之间功能联系的体外实验，从不同的层次多个角度研究这两种信号在口腔上皮干细胞向成釉细胞分化过程中的作用机制。研究结果可望丰富并揭示这两种信号分子在牙上皮细胞分化中的交互调控作用，增进对于釉质发育缺陷基因表达的网络调控的理解。同时也可为探讨CD133和Notch信号在其他相关疾病中的作用机制奠定基础。

Notch信号通路是细胞间相互作用以控制细胞命运的一种重要方式。CD133是一种在正常干细胞与肿瘤干细胞表面普遍表达的跨膜糖蛋白，近年来作为多种干细胞的表面标志而被重视。本课题以牙齿作为模型，研究了CD133在口腔上皮干细胞向成釉细胞分化过程中的作用机制，发现CD133与Notch信号途径存在交互作用；CD133的细胞内片段具有调节上皮细胞分化的功能，而这种功能是通过与RBP-Jk，即Notch信号系统的主要转录因子直接结合而获得的；同时也发现Notch信号系统在发挥调节牙上皮细胞命运的作用时亦需要CD133来协同完成。本研究对于这两种信号分子在上皮细胞发育、分化、增殖中的协同作用的发现，可使对于釉质发育缺陷基因表达的网络调控的理解提高到一个新的水平，同时也为探讨CD133和Notch信号在其他相关疾病中的作用机制奠定基础。