Nuclei are maintained at a defined position in many cell types. Proper nuclear position is physiologically important and abnormal nuclear position is known to be associated with disease. For example, central nuclei in muscle fibers is considered a hallmark of myopathies. Nuclear position is also regulated in migrating cells.In fibroblasts migrating on a two-dimensional surface, the nuclei usually reside in the rear of the cells. It was originally believed that this was a passive phenomenon: when cells are protruding, the nuclei, the largest organelle, naturally lag behind. However, experiments in the Gundersen lab at Columbia University showed that nucleus actively moves rearward before cell protrusion happens (see below), indicating that nuclear position is tightly regulated in migrating cells.
The molecular mechanism of nuclear movement in fibroblasts is well-studied. Binding of lysophosphatidic acid to its receptor activates the small GTPase cdc42, which in turn activates the formation of actin cables at the leading edge. These cables are powered by myosin IIA and steered by myosin IIB to move retrogradely. A linear nuclear structure composed of nesprin2-G and SUN2 (termed TAN line) couples the nucleus to moving actin cables, and the force to carry the nucleus backward.
It should be noted that nuclear position doesn’t always rely on actin cytoskeleton. In many systems nuclear movement is driven by microtubules and its motors. Rearward nuclear position is also not universal in migrating cells. In migrating leukocytes, the nuclei trend to locate in the front of the cell. It was shown that the nuclear membrane forms protrusions that probe their vicinity to help to determine the path of least resistance. The molecular detail of these nuclear protrusions are still unclear.
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