Niche-mediated regulation of asymmetric stem cell division

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

? DESCRIPTION (provided by applicant): Asymmetric division of adult stem cells that produces a self-renewing stem cell and a differentiating daughter cell is crucial for tissue homeostasis in diverse systems. Disruption of this balance is postulated to underlie many pathological conditions, including tumorigenesis/tissue hyperplasia (due to excess self-renewal) and tissue degeneration/aging (due to excess differentiation). Intensive investigations have revealed the mechanisms that polarize cells and orient the division plane to achieve asymmetric cell division; however, less is known about how cells might respond to perturbation of cell polarity and whether/how cells might correct such perturbation prior to cell division to ensure the asymmetric outcome of the division. Also, it has been speculated that the stem cell niche might regulate asymmetric stem cell division, in addition to its well-established role in specifying stem cell identity. However, due to the essential requirement of the stem cell niche in stem cell maintenance, the role of the niche in directing oriented, asymmetric stem cell division has never been directly tested. In this proposal, we aim to investigate the role of the stem cell niche in instructing oriented stem cell division, and the additional layer of the mechanism (the centrosome orientation checkpoint; COC) that further ensures asymmetric stem cell division using Drosophila male germline stem cells (GSCs) as a model system. Our preliminary study suggests two novel critical mechanisms that orient GSC spindles leading to asymmetric stem cell division. 1) The niche-derived self-renewal factor (Upd) regulates spindle orientation by directing the receptor-microtubule interaction, in addition to its well-known role as a self-renewa factor. 2) Bazooka/Par-3 forms a small subcellular structure, providing a docking site for the centrosomes to achieve the correct orientation, and such docking likely serves as a condition that satisfies the checkpoint that monitors the correct centrosome orientation. Successful completion of this proposal will reveal novel mechanisms for the asymmetric stem cell division and its checkpoint, contributing to our understanding of stem cell-mediated tissue homeostasis.