Synergistic role of Notch and CD133 in oral epithelial cell differentiation and survivalThe Notch signaling is an evolutionarily conserved pathway that regulates cell-cell communication and cell fate. CD133/Prominin1 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 my preliminary results, I hypothesize that Notch and CD133 play synergistic roles in regulating epithelial cell fates. Using the tooth as a model system, my 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 my 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, I 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. I 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. Initially focusing on tooth development, I plan to extend and assess the significance of the findings to oral mucosa keratinocyte stem cell renewal and differentiation. 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.