Elucidating the cytoskeletal mechanics in stem cell niche morphogenesis

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Project Abstract: Defects in stem cell function severely impact human health by inducing tumor formation or tissue degeneration. To maintain a proper balance of self-renewal and differentiation, stem cells rely on signaling cues from their niche, which is the microenvironment in which they reside. It is imperative to understand the intricacies that underlie niche biology to reveal mechanisms that promote normal stem cell function and minimize defects in human health. In many tissues, the niche has a precise and reproducible morphology. However, not much is known about how niche morphology is controlled or how it impacts niche function. This project will use the Drosophila gonad to study the mechanics of niche formation, combining genetic tractability with powerful live- imaging techniques pioneered in the DiNardo lab. In this system, the niche has a distinct morphology defined by a smoothened boundary between the niche and the adjacent stem cells. This boundary is further referred to as the niche periphery. Functionally, the niche plays key roles in regulating stem cell behavior: 1) it is the source for self-renewal cues, 2) it restricts access of these cues to only adjacent cells, and 3) it regulates stem cell division orientation. Preliminary evidence suggests that the smooth niche periphery is crucial to ensure proper division angles for germline stem cells (GSCs), suggesting a link between niche structure and function. Furthermore, F-actin and Myosin II (MyoII) are enriched at the niche periphery, accompanied by tensile forces, suggestive of actomyosin contractility. A key goal for this project is to unveil the role of actomyosin contractility in niche morphogenesis and function (Aim 1). Since niche morphogenesis is highly reproducible, this project will also address upstream mechanisms that robustly polarize F-actin and MyoII to the niche periphery (Aim 2). An intriguing possibility is that mechanical forces exerted on the niche by adherent GSCs induce cytoskeletal polarization along the niche periphery. Preliminary evidence suggests GSC divisions are required for proper niche morphology, and it is known that multiple forces act in concert to drive spindle elongation in a dividing cell. This project will address the Hypothesis that F-actin and MyoII enrichment along the niche periphery is induced by GSC spindle elongation, and is necessary for niche formation and function. A combination of transgenic techniques will be used to manipulate actomyosin contractility, as well as inhibit microtubule motors involved in spindle elongation. This project will potentially unveil a feedback mechanism where stem cells shape the niche that guides their behavior, and will be among the first to describe the mechanisms of shaping a functional niche. The training plan for this project consists of lab work, conference attendance, journal clubs, lab meetings, graduate group seminars, and exposure to teaching and mentoring roles. This work will be completed under the mentorship of Dr. Stephen DiNardo, an expert in Drosophila biology and morphogenesis, with co-mentorship by Dr. Erfei Bi, an expert on Myosin, actomyosin ring formation, and cell polarity.