This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. One of the emerging universal characteristics of stem cells/progenitors, including neural and retinal stem cells, is the preferential expression of ABCG2, a half transporter belonging to ATP-binding cassette (ABC) superfamily of transmembrane proteins. These transporters mediate efflux of a broad spectrum of substrates and their ability to preferentially exclude DNA intercalating dye, Hoechst 33342, is regarded to be the molecular basis for the enrichment of stem cells as side population (SP) of cells by fluorescence activated cell sorting. The decline of expression of ABCG2 with retinal differentiation suggests that ABCG2 expression is involved in the maintenance of stem cells, and this has been supported by perturbation of expression by transduction and by siRNA repression, which showed that the magnitude of the SP corresponded to the level of ABCG2 expression and maintenance of stem cell phenotype. We have hypothesized that ABCG2 is regulated through Notch signaling. Our preliminary studies have shown that Notch1 and ABCG2 colocalize, and that inhibition of Notch results in decreased expression of ABCG2 and cell differentiation. We also have evidence that activation of ABCG2 by Notch is mediated through CSL elements in the ABCG2 promotor. These results will be verified by in vivo experiments.
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