Stem cells are necessary for tissue homeostasis, and are often localized to specialized niches that control their function. In this manner, niches control virtually all aspects of stem cell dynamics, and these properties of stem cells are essential to tissue maintenance. Recent work has shown that precise cellular architecture is important in order for a niche to communicate with fidelity to the stem cells it controls. A major issue is that the field does not understand how niches are initially formed in a tissue, nor the key cell biological steps that constitute stem cell dynamics., and how these are regulated by niche signals. Our lab made significant advances on these questions over the past five years of GM funding. First, after identifying key signals and transcriptional regulators of niche cell specification, we revealed the dynamics of niche formation by live-imaging. This enabled us to suggest mechanisms underlying niche morphogenesis that are so central to its function. We pursue the underlying mechanisms in this proposal, capitalizing on our knowledge of cytoskeletal control over cell-cell organization, and in particular the involvement of actomyosin contractility and RhoA signaling. Second, we discovered that the niche imposes precise control over fundamental cellular processes such as abscission and midbody inheritance in order to regulate stem cell dynamics during tissue homeostasis and upon stresses, such as aging. We found that dysregulations of either of these fundamental cell biological processes compromises tissue function. Furthermore, the control of midbody inheritance as detailed in the proposal should have an impact generally on our understanding of how normal and cancer cells deal with defects in centrosome number. To address our hyptheses, we combine the powerful genetic and molecalur approaches available in using Drosohila, with state-of-the-art assays in cellualr mechanics, which include high spatial and temporal live-imaging, FRAP and laser ablation. Collectively, our approaches should reveal the undelying mechnics that establish a niche properly, and reveal important cellular features that allow stem cells to maintain tissues. !
There is intense interest in the circuits regulated by niches that guide stem cell behavior. It is not understood how the niche is specified and assembled in a tissue, and then how it executes control over the stem cell pool. Understanding these interactions will be crucial to the use of stem cells in regenerative medicine. !
