Thesis advisor: Eric S. Folker / Skeletal muscle is a syncytial cell type in which the multiple nuclei are evenly spaced along the cell periphery. During muscle development, the myonuclei undergo an elaborate set of movements to achieve this precise positioning throughout the muscle. The importance of proper nuclear positioning is highlighted by the correlation between mispositioned nuclei and muscle disease. However, the mechanisms that govern this energetically expensive process as well as the influence nuclear positioning has on muscle cell function remains to be elucidated. The goal of this thesis is to determine the molecular factors and subsequent mechanisms that regulate nuclear movement and how such pathways are disrupted in various muscle diseases. Since many of the key cellular features are conserved between Drosophila and mammalian muscles, we utilize Drosophila musculature as a model system to study myonuclear positioning during muscle development. In this thesis, we provide the first evidence that nuclei experience attractive and repulsive interactions with one another as they actively migrate. Furthermore, we demonstrate that these nucleus-nucleus interactions are critical for proper nuclear positioning, and that they are distinctly regulated by genes that are associated with two different muscle diseases, Emery-Dreifuss muscular dystrophy and Centronuclear myopathy (Chapter 2). We then elaborate upon the genetic mechanisms through which CNM-linked genes regulate nuclear positioning (Chapter 3). Finally, we show that proper nuclear movement requires both the separation of nuclei from their neighbors as well as the transmission of force, that is generated from the cytoskeleton, to move nuclei within the cell (Chapter 4). Together, the work presented in this thesis provides new perspective and mechanistic insights into the genetic factors and physical forces that regulate nuclear movement during muscle development and how such pathways are disrupted in disease, while emphasizing the importance of studying such dynamic processes within an in vivo system. / Thesis (PhD) — Boston College, 2020. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Biology.

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