Notch Regulation of Stem Cell Fate in Muscle

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DESCRIPTION (provided by applicant): Adult stem cells are defined by their capacity to differentiate into a specific tissue type while maintaining their own population through a 'self-renewal' process. A precise balance of the cell fate choice between self-renewal and differentiation is critical for stem cell function, tissue homeostasis and prevention of tumor formation. However, the molecular mechanisms regulating this process are unclear. Satellite cells in the skeletal muscle represent one of the few systems in which stem self- renewal and differentiation can be elegantly dissected. Specifically, satellite cells can asymmetrically generate self-renewal and committed daughter cells upon apical-basal, but not planar, oriented cell divisions. Our long-term goal is to understand how signals within the muscle regulate satellite cell self-renewal and differentiation, and utilize this knowledge to enhance satellite cell function and improve the repair of diseased muscles. Here, we aim to investigate the role of 'Notch' signaling in the regulation of muscle stem cell fate. The Notch signaling will be visualized using a transgenic mouse in which Notch-activated cells exhibit green fluorescence. We will then examine whether Notch signaling regulates stem cell fate and self-renewal in undamaged and regenerating muscles, respectively. We will further genetically activate or inactivate key components of the Notch signaling pathway and ask how this perturbation shifts the balance between stem cell self-renewal and differentiation. Finally, we will investigate the molecular regulation of Notch signaling in satellite cells. These studies may lead to development of novel therapeutic approaches to improve muscle repair in the aged and diseased muscles that are characterized by loss of stem cells. PUBLIC HEALTH RELEVANCE: Understanding how the developmental fate of muscle stem cells is regulated may lead to potential therapeutic approaches to enhance stem cell function and restore degenerated muscles caused by aging and muscle diseases, conditions that affect a quarter of Americans.