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Trendsetters
Department of Cell Biology and Anatomy, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan
Heinz Valtin
Editor, TRENDSETTERS
Our bodies are asymmetrical: the heart, spleen, and pancreas reside on the left, whereas the gallbladder and most of the liver are on the right. When this asymmetry is reversed, the condition is called situs inversus. Human patients with a genetic disorder called Kartagener's syndrome manifest not only situs inversus but also defective ciliary function leading to immobile sperm, bronchiectasis, and sinusitis. This fact has led to speculation that cilia may play a role in the determination of normal left-right (L-R) asymmetry. There is considerable experimental evidence suggesting that the node, a transient neural plate structure found in early embryos, may be important in determining L-R asymmetry (1). Nodal cells do, in fact, have a single cilium on their ventral surface, although until recently the cilium was thought to be immotile. This précis deals with a reevaluation of ciliary function of nodal cells in the determination of L-R asymmetry.
KIF3 belongs to the kinesin superfamily of proteins; it is a complex of microtubule-associated motor proteins essential for normal ciliary function. Mice in which this complex is deleted—so-called kif3A and kif3B knockout mice—manifest not only loss of nodal cilia but also loss of L-R asymmetry; their embryos show randomization of heart loops and tail turning, in contrast to embryos of control mice, which uniformly show dextroversion of heart loops and tails (2). Moreover, nodal cilia appear to be early determiners of asymmetry, preceding even the expression of lefty-2, one of the earliest left-defining genes (2). By videomicroscopy, it was shown that although nodal cells in wild-type mice have single cilia that are motile and generate a leftward flow of extraembryonic fluid, such cilia are very short or absent in kif3A and kif3B knockout mice. Finally, immunocytochemistry showed KIF3A and KIF3B to be localized in nodal monocilia of wild-type mice, suggesting that the KIF3 complexes may be essential for the formation of cilia in nodal cells.
The mechanism by which lack of monocilia in nodal cells leads to loss of L-R asymmetry has remained unclear. Most motile cilia move to and fro, whereas nodal cilia rotate, generating a leftward flow. The unique rotational movement may be a characteristic of primary monocilia. Fluorescent beads, placed in extraembryonic fluid close to the nodes, revealed unidirectional leftward flow in wild-type embryos (so-called nodal flow), whereas in embryos of knockout mice the beads showed only Brownian movement without unidirectional flow. Thus it is conceivable that nodal flow transports putative morphogens in a direction that leads to L-R asymmetry.
In summary, then, the results suggest that intraciliary transport of protein complexes such as tubulin leads to ciliogenesis by KIF3 and that the rotational movement of nodal cilia is essential for generating leftward nodal flow. This unidirectional flow conceivably could create concentration gradients for morphogens that are secreted from the nodal region and are responsible for L-R asymmetry. This view is supported by more recent experiments in spontaneously mutant mice, 50% of which have situs inversus (called "iv mice," for inversus viscerum). Mutation of a gene called lrd (left-right dynein) is responsible for the randomness of L-R asymmetry in these mice. Expression of lrd is limited to nodal cells at 7.5 days of gestation. In heterozygous embryos (iv/+), nodal cilia rotated rapidly at ~600 rotations/min (the same rate as in wild-type mice) and produced a rapid (20–50 µm/s), smooth leftward flow of extraembryonic fluid in the region of the node (3). However, in embryos of the mutant homozygotes (iv/iv), the nodal cilia appeared very rigid and there was no nodal flow (3). Thus motor proteins such as KIF3 play important roles in L-R asymmetry, and by extension, very likely in other developmental events as well.
Footnotes
In this section we feature some of the latest and most striking new findings in physiology, interpreting the term "physiology" in its broadest sense. In each instance, an effort will be made to place the new findings in perspective.
References
| Occasionally, the Editor of the Trendsetters section invites contributions from the authors of published scientific articles that have been identified as being of special interest. All précis to Trendsetters are by invitation only. |
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