Year 4

Stem cells are the building blocks during development of organisms as varied as plants and humans. In addition, adult or “tissue” stem cells provide for the maintenance and regeneration of tissues, such as blood and skin throughout the lifetime of an individual. The ability of stem cells to contribute to these processes depends on their unique ability to divide and generate both new stem cells (self-renewal) as well as specialized cell types (differentiation). A thorough understanding of the factors that regulate self-renewal programs will be essential for the expansion and long-term maintenance of adult stem cells in culture, a necessary step towards the successful use of stem cells in regenerative medicine and tissue replacement therapies. This proposal seeks to uncover the mechanisms that endow stem cells with the ability to self-renew using the fruit fly Drosophila melanogaster as well as pluripotent human cells.
In the most recent funding period, we have characterized the role of a gene called multiple sex combs (mxc), which plays a role in regulating the switch between proliferation and differentiation via control of proteins that are essential for proper DNA compaction and, consequently, gene expression; these genes are called histones. However, we have made the surprising finding that the protein encoded by mxc can regulate the expression of genes, in addition to histones. We have shown that this gene is required for maintenance of three different stem cell populations in flies; however, the mechanism by which Mxc regulates stem cell maintenance varies for each stem cell population. Because the function of this gene is conserved in human cells, we speculate that understanding the function of this gene will provide insight into additional mechanisms that regulate the behavior of human stem cells.
In addition, we have characterized the role of human Igf-II mRNA binding protein 1 (hIMP1) in pluripotent human cells and found that it regulates the expression of key proteins that maintain the pluripotent state and, thus, regulates the ability of these cells to give rise to specific tissues during development.
Lastly, we have developed a system for investigating maintenance and regeneration of specialized stem cell microenvironments in the Drosophila male germ line. Regeneration of stem cell environments (also known as ‘niches’) must accompany the expansion of stem cells required for tissue repair. Thus, investigating this process will lead to the identification of genes and pathways that regulate regeneration of stem cells in more complex mammalian tissues.