Asymmetric cell division is at the heart of organismal development and maintenance. All multicellular organisms develop through a series of such cell divisions. Adult tissues maintenance is sustained by adult stem cells, which often divide asymmetrically to produce a stem cell and a differentiating cell. Defects in asymmetric cell division can lead to failure in organismal development and to pathologies such as cancer and degenerative diseases. To understand the mechanisms involved in the generation of fate asymmetry and tissue homeostasis, our laboratory studies asymmetric stem cell division in the Drosophila male germline. Our goal is to provide fundamental insights into the mechanisms that govern cell asymmetry, using stem cells as a genetically tractable model system at the level of single-cell and subcellular resolution.
Centrosome Orientation During Asymmetric Stem Cell Division in the Drosophila Male Germline
Asymmetric stem cell division is a fundamental mechanism that balances stem cell self-renewal and differentiation. Drosophila male germline stem cells (GSCs) divide asymmetrically by orienting their mitotic spindle toward the hub cells, major components in the stem cell niche that specifies GSC identity. We have shown that stereotypical centrosome positioning is the key to oriented GSC divisions (Figure 1). Such centrosome positioning is ensured by the age difference between mother and daughter centrosomes: the mother centrosome with higher microtubule-organizing center activity remains close to hub cells; the daughter centrosome migrates to the other side of the GSCs in preparation for oriented divisions. These observations provided the first example in which the differences between mother and daughter centrosomes are utilized in the context of developmental biology and stem cell behavior.
Stereotypical behavior of the centrosomes in GSCs suggests the importance of centrosome function during stem cell division. We have found that GSCs possess a novel checkpoint that monitors the correct centrosome orientation. This centrosome orientation checkpoint is responsible for arresting the cell cycle when a centrosome is misoriented, thus preventing GSC division that might yield two stem cells instead of a stem cell and a differentiating cell. This checkpoint functions as an additional regulatory layer of the mechanism to ensure proper asymmetric stem cell division. While such a checkpoint benefits the organism by preventing overproliferation of stem cells, we showed that this checkpoint may also contribute to tissue aging through decreased GSC proliferation because stem cells with misoriented centrosomes accumulate with age. This suggests that certain aspects of aging may result from the trade-off associated with maintaining robust tissue homeostasis in the earlier stages of an organism's life. Furthermore, we found that GSC misorientation increases when nutrients are limited, leading to cell cycle arrest and slowing of stem cell division thus preserving GSC number under conditions of nutritional stress. To date, our efforts to characterize the centrosome orientation checkpoint at the molecular level have resulted in the identification of several new components of the checkpoint, including the polarity kinase Par-1 and its known substrate, Par-3/Bazooka (Baz).
Stem cell-niche communication via microtubule-based (MT)-nanotubes
Many adult stem cells reside in specialized microenvironments referred to as niches. Niches produce a variety of signaling molecules and growth factors that maintain the residing stem cells in an undifferentiated state. Current models suggest that niche signaling is short-range in nature, thus limiting the self-renewal capacity and proliferation of stem cells to a physically confined space. Restraining niche signaling in this way likely prevents over-proliferation of stem cells, thus reducing the likelihood of tumorigenesis. Despite the appeal of these models, stem cell-niche signaling often involves ligand-receptor combinations that, in other contexts, are thought to act over relatively long distances. The mechanisms that spatially confine stem cell-niche signaling and prevent non-stem cells from gaining access to these self-renewing signals remain poorly understood. We have recently discovered a thin, microtubule-based protrusion that extends from germline stem cells (GSCs) into hub cells (Figure 2). We refer to these protrusions as microtubule based (MT)-nanotubes to reflect their structural similarity to tunneling nanotubes characterized in other systems including mammals. Our studies showed that BMP signaling (Dpp ligand-Tkv receptor) is mediated by MT-nanotubes. We propose that MT-nanotubes function to mediate productive niche signaling such that only stem cells experience a sufficient amount of niche-dependent signal transduction, ensuring both stem cell self-renewal and timely differentiation of daughter cells.
Grants from the National Institutes of Health provided partial support for some of these projects.
As of February 25, 2016