Our research focuses on the roles of the nucleus in orchestrating developmental and cellular processes. Specifically, we investigate the mechanisms that regulate nuclear movement in skeletal muscle and the impact of such movements within the context of myogenesis, muscle function, and muscle disease pathogenesis.
Nuclear Movement: a conserved process
In most text books the cell nucleus is depicted as a static sphere occupying space near the center of the cell. This depiction is extremely misleading. The nucleus is a highly mobile organelle that occupies precise positions within each cell dependent on cell type, developmental stage, and cellular activity. Despite the conservation of dynamic nuclear movements amongst cell types and amongst species, the mechanisms of nuclear movement are only now emerging. Furthermore, little is known about how nuclear movement contributes to tissue development and function.
Myonuclear Movement in Skeletal Muscle
Skeletal muscle is a tissue type of special interest with regards to nuclear movement. Muscle cells are syncytial containing numerous nuclei, each of which undergoes several distinct movements. After fusion, new nuclei are incorporated from mononucleated myoblasts and rapidly move to the center of the myotube, where they associate with the already incorporated nuclei. As the myotube matures into a myofiber during the final stages of muscle differentiation, nuclei move out to the periphery of the muscle. The end result is that most of the nuclei reside at the periphery of the muscle cell, and evenly spaced such that the distance between nuclei is maximized, with a small percentage of nuclei clustered at neuromuscular junctions. During muscle repair, newly incorporated nuclei undergo a similar set of movements. This precise positioning of nuclei in muscle cells is disrupted in patients with disparate forms of muscle disease, suggesting that proper movement and positioning of nuclei is essential to muscle development and function.
Schematic cross section of skeletal muscle during development and repair. During development, new nuclei (green) are incorporated from myoblasts during fusion and then actively move towards other nuclei in the center of the myotube (magenta). As the myotube matures into a myofiber, nuclei move from the center to the periphery of the muscle to maximize their distance from one another. Nuclei undergo a similar set of movement during muscle repair, where nuclei first move in towards the center of the muscle fiber before moving back out to the periphery of the cell.
Muscular Dystrophies & Diseases
The importance of myonuclear positioning is highlighted by the high correlation between muscle disease and mispositioned nuclei. In healthy individuals, nuclei are precisely arranged at the periphery of the cell to maximize the distance between nuclei. In patients with various muscle dystrophies, nuclei are aberrantly positioned. Nuclei are found either clustered together out in the muscle periphery or mispositioned within the center of the myofiber. Although the relationship between the mispositioned nuclei and disease have been noted for decades, the mechanisms of nuclear movement have only recently begun to emerge. We aim to understand how nuclei move in healthy cells, why they are mispositioned in diseased cells, and how mispositioned nuclei impact muscle function.
Schematic cross section of muscle fibers (magenta) and nuclei (green). The cartoon on the left represents a healthy muscle where nuclei positioned evenly around the periphery of the myofibers. In contrast, the cartoon on the right presents a diseased muscle, where nuclei are irregularly spaced around the periphery, with some nuclei mispositioned in the center of the myofiber.
Our model organism: Drosophila melanogaster
To understand how and why nuclei move, we utilize the model system Drosophila melanogaster. The cellular structure of muscle is conserved between Drosophila and humans. Both are multinucleated cells that position their nuclei to maximize the internuclear distance. However, Drosophila muscle cells offer superior genetic, optical, and physiological tractability. Mammalian muscles are composed of complex bundles of cells whereas in Drosophila embryos, individual muscle cells are fully functional muscles. This difference allows us to image and measure the precise positions of nuclei within each cell. We capitalize on these advantages to perform genetic screens, advanced imaging in the developing organism, and functional output assays to define the mechanisms of nuclear movement and the determine how nuclear movement impacts muscle architecture and function. Specifically, we use the Drosophila embryo to identify the genes that are required to move nuclei during early muscle development and regulate the initial establishment of muscle structure. Additionally, the Drosophila larva is used to identify the genes and processes that are necessary to maintain the cellular structure during rapid muscle growth.
Folker Lab 