Stem cells must self-renew and produce daughters that differentiate. Consequently, stem cells are generally supported only in restricted locations that regulate proliferation and direct appropriate daughter cell fates. Somatic follicle stem cells (FSCs) in the Drosophila ovary provide an exceptional opportunity to study how the niche environment regulates stem cell behavior. Key advantages of the FSC model include advanced knowledge of regulation by multiple signaling pathways, an important role of competition between stem cells, and regulation of both niche adhesion and proliferation as key parameters of stem cell maintenance. Both the general principles discovered about FSC dynamics and regulation, as well as the impact of specific signaling pathways will provide important insights fo understanding the normal regulation of mammalian epithelial stem cells and how pre-cancerous mutations that arise in stem cells are selected and amplified. This proposal aims first to employ multiple genetic methods for lineage tracing together with a marker of cellular proliferative histories and live imaging to extend recent studies that promise a substantial advance in our understanding of FSC numbers, arrangement and dynamics. The anticipated outcomes would reveal remarkable similarities to the dynamics of mammalian intestinal stem cells. They would also explain why FSC maintenance and competition depends critically on proliferation and would show three potential fates of FSC daughters correlated with the direction of cell migration. The proliferative contribution of relevant signaling pathways will be defined and mechanistic connections will be investigated. Specific hypotheses that Wnt and JAK-STAT signaling pathways guide FSC derivative migration and fates, and that integrins may mediate some effects of JAK-STAT signaling will be tested. Finally, transcriptional responses to signaling pathways in FSCs will be measured as part of an overall objective to understand both the general principles and the molecular steps by which the niche environment regulates FSC behaviors that fit their specific physiological purpose.
Stem cells are key vehicles for future regenerative therapies and are critical cells for the earliest steps of development of many cancers, yet very little are known about how stem cells are regulated. We propose to continue our studies of adult stem cells in the model genetic organism, Drosophila, in order to uncover basic principles of stem cell regulation that are directly relevant, and of critical significance, to our understanding of how to harness human stem cells in medicine and how to combat cancer.
|Huang, Jianhua; Kalderon, Daniel (2014) Coupling of Hedgehog and Hippo pathways promotes stem cell maintenance by stimulating proliferation. J Cell Biol 205:325-38|
|Vied, Cynthia; Reilein, Amy; Field, Natania S et al. (2012) Regulation of stem cells by intersecting gradients of long-range niche signals. Dev Cell 23:836-48|
|Wang, Zhu A; Huang, Jianhua; Kalderon, Daniel (2012) Drosophila follicle stem cells are regulated by proliferation and niche adhesion as well as mitochondria and ROS. Nat Commun 3:769|