Vertebrate animals, such as zebrafish, use Adult Stem Cells (ASCs) to grow the adult from the embryo and for homeostasis and repair of its constitutive tissues. Defects in ASCs are responsible for a variety of diseases and syndromes, including aplastic anemias and hair graying. We have developed the zebrafish melanocyte stem cell (MSC) as a model for studying ASC regulation. In this proposal, we develop clonal labeling techniques to investigate how the MSC segregates from Direct-Developing lineages in the forming neural crest, and how different molecular mechanisms control different aspects of MSC regulation. A key feature of some ASCs, as well as cancer stem cells, is the transitions between proliferative and quiescent states. In the zebrafish larvae, melanocyte development is largely completed by 3 days post fertilization (dpf). Differentiated melanocytes repress, or impose quiescence, on MSC, preventing melanocyte development after 3dpf. We have identified drugs that cause development of excess melanocytes in the larval zebrafish. We will test the hypothesis that these drugs act to relieve repression, transiting the MSC from quiescence to proliferation. We will also ask whether repression-relieving drugs sensitize the quiescent MSC to cell cycle-dependent chemotherapeutics such as oxaliplatin. We will use our assay to distinguish between late developing excess melanocytes from early melanocytes to perform an unbiased screen for mutations in genes that regulate repression and quiescence in the MSC.
Growth, homeostasis and repair of the adult animal is performed by Adult Stem Cells (ASCs). Defects in the regulation of ASCs are responsible for diseases or syndromes such as anaplastic anemia or hair graying. Properties of quiescence and proliferation of ASCs are likely shared by cancer cells and may explain resistance of cancers to cell cycle-dependent chemotherapies. We study the Melanocyte Stem Cell, an ASC in the zebrafish larvae. This project focuses on segregation of stem cell fates in the embryo, in identifying molecular mechanisms responsible for different aspects of ASC regulation, and how quiescence is maintained in the ASC.
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