|Maselli, A. G., Davis, R.,
Furukawa, R. & Fechheimer, M. (2002) Formation of Hirano bodies in Dictyostelium
and mammalian cells induces by expression of a modified form of an
actin-crosslinking protein., J.Cell Sci. 115, 1939-1952.
|We report the serendipitous
development of the first cultured cell models of Hirano bodies.
Myc-epitope-tagged forms of the 34 kDa actin bundling protein (amino
acids 1-295) and the CT fragment (amino acids 124-295) of the 34 kDa
protein that exhibits activated actin binding and calcium-insensitive
actin filament crosslinking activity were expressed in Dictyostelium and
mammalian cells to assess the behavior of these modified forms in vivo.
Dictyostelium cells expressing the CT-myc fragment: (1) form ellipsoidal
regions that contain ordered assemblies of F-actin, CT-myc, myosin II,
cofilin and alpha-actinin; (2) grow and develop more slowly than
wildtype, but produce normal morphogenetic structures; (3) perform
pinocytosis and phagocytosis normally; and (4) produce a level of total
actin equivalent to wildtype, but a higher level of F-actin. The
paracrystalline inclusions bear a striking resemblance to Hirano bodies,
which are associated with a number of pathological conditions.
Furthermore, expression of the CT fragment in murine L cells results in
F-actin rearrangements characterized by loss of stress fibers,
accumulation of numerous punctate foci, and large perinuclear
aggregates, the Hirano bodies. Thus, failure to regulate the activity
and/or affinity of an actin crosslinking protein can provide a signal
for formation of Hirano bodies. More generally, formation of Hirano
bodies is a cellular response to or a consequence of aberrant function
of the actin cytoskeleton. The results reveal that formation of Hirano
bodies is not necessarily related to cell death. These cultured cell
models should facilitate studies of the biochemistry, genetics and
physiological effects of Hirano bodies.