Nuclear movement

Posted on by Wakam Chang

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.

A movie of NIH3T3 fibroblasts expressing GFP-tubulin, time: minute after the addition of lysophosphatidic acid. From Gomes et. al, Cell 2005.

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.

A movie of NIH3T3 fibroblasts expressing GFP-Progerin and mCherry-LifeAct, time: h:mm after addition of lysophosphatidic acid. Progerin is a mutated nuclear lamina protein. Nuclear lamina with progerin is not strong enough to support nuclear movement. As a result, progerin-containing TAN lines slip over an immobile nucleus. From Chang et. al, PNAS 2019.

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.

Reference

  • Chang W, Folker ES, Worman HJ, Gundersen GG. Emerin organizes actin flow for nuclear movement and centrosome orientation in migrating fibroblasts. Mol Biol Cell, 2013 Dec; 24(24):3869-80.
  • Chang W, Wang Y, Luxton GWG, Östlund C, Worman HJ, Gundersen GG. Imbalanced nucleocytoskeletal connections create common polarity defects in progeria and physiological aging. Proceedings of the National Academy of Sciences of the USA, 2019 Feb 26; 116(9):3578-3583.
  • Folker ES, Ostlund C, Luxton GW, Worman HJ, Gundersen GG. Lamin A variants that cause striated muscle disease are defective in anchoring transmembrane actin-associated nuclear lines for nuclear movement. Proc Natl Acad Sci U S A, 2011 Jan; 108(1):131-6.
  • Gomes ER, Jani S, Gundersen GG. Nuclear movement regulated by Cdc42, MRCK, myosin, and actin flow establishes MTOC polarization in migrating cells. Cell, 2005 May; 121(3):451-63.
  • Gundersen GG, Worman HJ.. Nuclear positioning. Cell, 2013 Mar; 152(6):1376-89.
  • Luxton GW, Gomes ER, Folker ES, Vintinner E, Gundersen GG. Linear arrays of nuclear envelope proteins harness retrograde actin flow for nuclear movement. Science, 2010 Aug; 329(5994):956-9.
  • Renkawitz J, Kopf A, Stopp J, de Vries I, Driscoll MK, Merrin J, Hauschild R, Welf ES, Danuser G, Fiolka R, Sixt M. Nuclear positioning facilitates amoeboid migration along the path of least resistance. Nature, 2019 Apr; 568(7753):546-550.