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Figure 1 - Regulation of nuclear movement in migrating fibroblasts.






Figure 2 - Nuclear movement during myofiber formation. 

Mechanisms of nuclear position  

There are at least two mechanisms that contribute to nuclear positioning:  one involves cytoplasmic dynein and microtubules and the other involves myosin II and actin.

Microtubule-dependent nuclear position
Dynein and microtubule-dependent nuclear movements frequently involve cortically anchored dynein that moves nuclei by pulling on microtubule that are associated with the nucleus through the centrosome. In some systems, dynein anchored to the nucleus can also contribute to nuclear movements.

Actin-dependent nuclear position
There are fewer examples of nuclear position events that involve the actin cytoskeleton. The nucleus can be clustered to the actin cytoskeleton by nesprins and nuclear movement is driven by myosin-II-dependent  forces such as actin retrograde flow during cell migration

Nuclear positioning during cell migration

During polarized cell migration, the nucleus becomes positioned away from the leading edge in mechanism that is dependent on actin retrograde flow. Nuclear movement is regulated by Cdc42, a small RhoGTPase, and its effector MRCK (myotonic dystrophy kinase-related Cdc42-binding kinase). MRCK phosphorylates and activates myosin II, resulting in nuclear movement away from the leading edge. This work suggests that the nucleus is moved by actin cytoskeleton (Figure 1)(Gomes et al. 2005)

We are investigating how actin retrograde flow drives nuclear movement away from the leading edge and how nuclear positioning regulates polarized cell migration.


Nuclear positioning events during myofiber differentiation

In mature myofiber, nuclei are positioned at the periphery of the cell with some nuclei clustered at the neuromuscular synapse. However, in immature myofibers, the nuclei accumulate at the cell center. Based on these observations, at least three nuclear movements or positioning events are predicted to occur during muscle fiber formation: 1) During syncytial myotube formation, the nuclei of mononucleated myoblasts move from the site of fusion to the center of the myotube; 2) During myofiber formation, the nuclei move from the center of the myotube to the cell periphery, and 3) During neuromuscular synapse formation, some nuclei become anchored close to the clusters of acetylcholine receptor (AchR), precursors of neuromuscular synapses (Fig. 2).  

We want to identify the mechanisms and the molecular pathways that regulate these different nuclear movement and position events.  We will then be able to study the role of nuclear positioning during myofiber formation and function. 

We are also interested in understanding how mutations in different proteins that are associated with muscular dystrophies are involved in nuclear position.