The Mechanisms and Function of Myonuclear Movement

Abstract

During muscle development, myonuclei undergo a complex set of movements that result in evenly spaced nuclei throughout the muscle cell. In many muscle diseases mispositioned myonuclei have been used as a hallmark phenotype of disease. A number of studies over the last decade have started to piece together the cytoskeletal elements that govern these movements. In Drosophila, two separate pools of Kinesin and Dynein work in synchrony to drive nuclear movement. However, it is still not clear how these two pools of microtubule motors become specified. In addition, it is not clear how nuclear position impacts the other defining feature of the muscle cell, which is the highly organized contractile network of sarcomeres. Previously, mispositioned myonuclei have been correlated with improper muscle function, yet no direct link between nuclear position and sarcomere development or function has been demonstrated. In this thesis, we show a role for Aplip1 (the Drosophila homolog of JIP1), a known regulator of both Kinesin and Dynein, in myonuclear positioning. Aplip1 localizes to the myotendinous junction and has genetically separable roles in myonuclear positioning and muscle stability. Furthermore, we show that a number of sarcomeric proteins, including ZASP, Actin and β-integrin localize to the nucleus prior to being incorporated into the sarcomere, regardless of nuclear position. Finally, we show that the LINC complex is required for nuclear dependent sarcomere assembly and that disruption of nuclear dependent sarcomere assembly or nuclear position resulted in a compromised sarcomeric network. Together, this thesis adds to the mechanisms that are important in positioning nuclei and shows the first direct link between the nucleus and sarcomere assembly.