Unconventional class I myosin motors implicated in establishment of situs inversus
By Jeffrey M. Perkel | April 6, 2006
A molecular motor appears to help form the left-right asymmetry axis in Drosophila, according to a pair of studies [ref 1, ref 2] published this week in Nature. Both papers show that mutation of a gene encoding the unconventional class I myosin, Myo31DF, results in situs inversus of the gut, testis, and spermiduct -- the first such mutant to be found in flies, and the first in any organism to involve myosin motors.
These findings likely provide important clues to the workings of the machinery that establishes symmetry in the developing embryo, a little-known aspect of invertebrate biology, Stéphane Noselli, of the University of Nice Sophia-Antipolis, lead author of the one of the studies and co-author of the other, told The Scientist.
Situs inversus is a reversal of an organism?s normal left-right asymmetry, placing the human heart on the right side of the chest, for instance. ?Left-right asymmetry is a secondary axis, which is set up after the anterior-posterior and dorsal-ventral axes,? Noselli said. ?This is an important axis because it is involved in the morphogenesis of most of the organs and viscera.? Deficiencies in left-right asymmetry can lead to congenital defects and miscarriage, he added.
Using different organ systems -- Noselli?s group focused on the directional looping of the spermiduct around the gut, while the other team, lead by Kenji Matsuno of the Tokyo University of Science, focused on the gut and testes -- the two teams identified Myo31DF as a primary determinant of left-right asymmetry in the fruit fly. Using RNA interference, Noselli?s group pinpointed the A8 segment of the genital disc as that tissue?s left-right organizer, or region that defines a tissue?s left-right asymmetry.
Matsuno?s team also implicated a second class I myosin, Myo61F, in the formation of the left-right axis. But where inhibition of 31DF causes situs inversus, so too does overexpression of 61F.
Class I myosins are molecular motors that ferry cargoes toward the plus-ends of actin filaments, the ?rails? upon which all myosins move. Though neither 31DF nor 61F has been formally shown to actually move along actin filaments, both proteins are known to bind actin in an ATP-dependent manner. In the current study Matsuno?s group demonstrated that disruption of the cell?s actin network randomized left-right symmetry. Based on these observations, he hypothesized that the two motors antagonize each other (that is, they carry antagonistic cargoes) to establish left-right polarity. ?We speculate that left-right asymmetry is relying on the myosin function, and myosin function depends on the actin cytoskeleton,? Matsuno told The Scientist.
?The model they propose is an interesting one,? said Mark Mooseker, the Ross Granville Harrison Professor of Molecular, Cellular & Developmental Biology, Cell Biology, and Pathology at Yale University, whose team cloned and cytologically characterized both myosins in 1995. ?They?ve got both myosins moving toward the plus ends of filaments, but one?s carrying a repressor cargo and one?s carrying an activator cargo, and the two together define a boundary, presumably, in space and time.?
How applicable these results will be to left-right asymmetry in vertebrates is unclear. Vertebrate left-right axes appear to be established primarily through the movement of signaling molecules by the beating of cilia. ?There is no evidence so far in vertebrates that myosin would be involved in left-right asymmetry,? Noselli noted. Myosins could, however, play a role in placement and morphogenesis of individual organs in vertebrates, according to Rebecca Burdine, an assistant professor of molecular biology at Princeton University, who studies left-right asymmetry in zebrafish. ?I don?t read these papers and think, ?wow, my lab has to go out and clone myosins because that?s going to be important for situs inversus in fish.? I bet it has no role at all. But they might have a role in how the heart loops to the right, or how the gut turns asymmetrically.?
Noselli?s team, however, has already uncovered hints for how this research may apply to vertebrates. Using yeast two-hybrid assays the group identified several Myo31DF binding partners, including beta-catenin, a protein that also binds the mouse situs inversus protein, Inversin. Beta-catenin also colocalized with Myo31DF at the adherens junctions in A8. That, Noselli said, suggests a model in which situs inversus genes control left-right asymmetry through a common mechanism involving the adherens junction. ?This is quite important,? Noselli said, ?because it helps in making a link between flies and vertebrates.?
Jeffrey M. Perkel
Links for this article
S. Hozumi et al., ?An unconventional myosin in Drosophila reverses the default handedness in visceral organs,? Nature, April 6, 2006
P. Speder et al., ?Type ID unconventional myosin controls left-right asymmetry in Drosophila,? Nature, April 6, 2006.
M. Stephan, ?Chasing the cilium,? The Scientist, October 11, 2004.
J.M. Perkel, ?Investigating molecular motors step by step,? The Scientist, March 15, 2004.