Aging and the nuclear lamina in mitotic stem cells

点击翻译按钮获取中文摘要

PROJECT SUMMARY Tissue homeostasis depends upon the regulated production of differentiated cells to replace those that are damaged or defective. Homeostasis declines with age, largely because of decreases in stem cell number and/or function. To intervene in the aging process, it is critical to understand mechanisms involved in stem cell homeostasis. We discovered that paradigmatic Drosophila female germline stem cells (fGSCs) use a non-canonical mode of mitosis, wherein the nuclear envelope and nuclear lamina remain throughout mitosis. In this mode, mitotic spindles are nucleated from centrosomes embedded in the retained nuclear lamina. This mode of mitosis has gone unrecognized, due to the rarity of stem cell divisions and the globally accepted assumption that metazoan mitoses involve nuclear lamina dispersal. As such, how the mitotic nuclear lamina impacts asymmetric stem cell divisions and stem cell maintenance is unknown. The long-term goal of these studies is to define contributions of the mitotic nuclear lamina to fGSC homeostasis during aging. We capitalize on this natural in vivo stem cell population that demonstrates rapid, age-dependent declines in stem cell functions to address two aims. Aim 1 will define how biological aging affects the mitotic nuclear lamina. Aim 2 will define the role of the nuclear lamina checkpoint kinases in physiological aging. Experiments in this proposal will establish contributions of the newly identified mitotic nuclear lamina to stem cell maintenance. These studies have the potential to provide insights into lamin associated diseases such as progeria and provide insights to advance therapeutics that delay or eliminate stem cell loss during natural aging.