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CELL BIOLOGY: ON LEFT-RIGHT ASYMMETRY IN SNAILS

The following points are made by J. Wandelt and L.M. Nagy (Current Biology 2004 14:R654):

1) Metazoans, by and large, possess a simple bilateral symmetry. This symmetry is, however, rarely perfect. Most animals exhibit a distinct left-right asymmetry of some internal organs, while appearing bilaterally symmetric on the outside. For example, vertebrates show asymmetries in the position and morphology of the heart, liver, and gut, whereas in nematodes, structures such as the gonad and intestine are asymmetric [1,2]. Snails (Gastropoda), however, are unusual in their asymmetric external appearance, which is apparent in the way the shell coils. If the shell is viewed from the side and its tip is held upright, the opening of the shell can be either to the left-hand side (sinistral) or to the right-hand side (dextral) of the midline.

2) Most gastropod species show a uniform handedness, and reversal of this asymmetry is rare in nature. Most snail species are dextral, except, for example, the common pond snail Physa, which is an entirely sinistral species. Another common pond snail, Lymnaea is notable in that both dextral and sinistral forms are found in nature, with sinistral individuals representing up to 2% of the population. Consequently, Lymnaea and Physa have long been handy models for studying the genetics and development of left-right asymmetry.

3) Left-right asymmetry can be traced back as far as the first division in the spiral cleavage pattern of snail embryos [4,5]. Spiral cleavage is characterized by the oblique angle of the early cleavage planes and the alternation of direction of successive divisions. Thus, if odd numbered divisions are oriented clockwise (dextrotropic), the even divisions are counter-clockwise (levotropic). For reasons that remain unknown, the cleavage geometry correlates almost perfectly with adult handedness.

4) H.E. Crampton (1894) was among the first to describe how cleavages in sinistral Physa and dextral Lymnaea embryos were the mirror-image pattern of one another. He attributed the reversed orientation of division to a reversal of spindle inclination and cleavage plane, as did Freeman and Lundelius (1982) in their observations of dextral and sinistral embryos that occur within a single species of Lymnaea. In this view, spiral cleavage is controlled by an asymmetry in the cortex that regulates the inclination of the mitotic apparatus prior to cytokinesis. By contrast, Meshcheryakov and Beloussov (5) attributed the reversal of cleavage pattern between sinistral and dextral species to a reversal -- from clockwise to anti-clockwise -- of the spiral rotation of the daughter micromeres during cytokinesis. These rotations were independent of the orientation of the spindle. According to both models, the reversal of handedness is caused by a reversal of cellular machinery. The discrepancies between these two views have yet to be resolved.

5) Shibazaki et al (3) approach the question of handedness through a detailed analysis of the cytoskeletal dynamics during early cleavage in Physa and Lymnaea. They observe that in dextrally cleaving Lymnaea embryos, the mitotic spindles are oriented in a clockwise direction (when viewed from the animal pole) during metaphase-anaphase. At this stage, they also observe that the cells protrude, or deform, along the same axis as the spindle. The sinistral embryos of Physa show similar changes of spindle orientation and overall cell shape, but in the reverse direction.

6) The work of Shibazaki et al (3) demonstrates that there is presumably more than one way to generate and revert the spiral cleavage pattern. While spindle inclination and micromere rotation have been described previously [4,5], this is the first report to implicate the two mechanisms in the reversal of handedness within one species.

References (abridged):

1. Mercola, M. (2003). Left-right asymmetry: Nodal points. J. Cell Sci. 116, 3251-3257

2. Wood, W.B. (1998). Handed asymmetry in nematodes. Cell Dev. Biol. 9, 53-60

3. Shibazaki, Y.X Shimizu, M. and Kuroda, R. (2004). Body handedness is directed by genetically-determined cytoskeletal dynamics in the early embryo. Curr. Biol. 14:1462

4. Conklin, E.G. (1902). Karyokinesis and cytokinesis in the maturation, fertilization and cleavage of Crepidula and other Gasteropoda. J. Acad. Nat. Sci. Phil. 12, 1-121

5. Meshcheryakov, V.N. and Beloussov, L.V. (1975). Asymmetrical rotations of blastomeres in early cleavage of gastropoda. Wilhem Roux's Arch. 177, 193-203

Current Biology http://www.current-biology.com

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CELL BIOLOGY: ON MICROTUBULE ASYMMETRY

The following points are made by G.G. Gundersen and A. Bretscher (Science 2003 300:2040):

1) Bacteria, yeast, and most mammalian cells exhibit polarity, that is, their proteins, lipids, and organelles are distributed asymmetrically between one end of the cell and the other. Establishing this asymmetry frequently depends on microtubules that respond to cues in the cell periphery. The prevailing search-and-capture model, elaborated by Kirschner and Mitchison 17 years ago, postulates that randomly assembled dynamic microtubules probe the cell cortex and are stabilized when they encounter localized cortical factors. However, a different picture is offered by recent studies in budding yeast that investigate the microtubule-dependent orientation of the spindle during the early stages of cell division. These studies suggest that a cortical factor -- previously thought to be positioned independently of microtubules -- interacts with a specific microtubule organizing center before migrating to the tips of the associated microtubules. The newly decorated microtubule ends, rather than randomly probing the cortex, are selected when myosin V binds to the cortical factor and then "marches" the microtubule ends along polarized actin cables toward the cortex. This model might also be applicable to the microtubules of animal cells.

2) In budding yeast, the axis of cell division is defined by the site of bud emergence, which is chosen early in the G1 phase of the cell cycle. Cells entering the cell cycle have a single microtubule organizing center called the spindle pole body (SPB), which is embedded in the nuclear envelope from which cytoplasmic microtubules emerge. The SPB duplicates itself and separates, giving rise to a second set of cytoplasmic microtubules and the intranuclear spindle. The initial step in spindle orientation occurs when microtubules from the "old" SPB are preferentially selected to become attached to the bud neck or bud tip. This process requires the cortical factor known as Kar9. All three of the new studies use high-resolution imaging techniques combined with genetic analysis to address how this initial orientation is achieved.

3) The new studies shift our view of how microtubule dynamics contribute to generating cellular asymmetries. They point to the guiding of microtubules by actin microfilaments through factors that initially interact separately with the two elements. The dynamics of microtubules are still likely to be important in this new view, especially because the myosin "target" is one that moves along actin cables. The authors suggest it will be interesting to test this model in other systems, such as migrating cells, neuronal growth cones, or polarized epithelia, where actin microfilaments and microtubules collaborate to effect cellular asymmetries.

Science http://www.sciencemag.org

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ON EMBRYOLOGICAL ASYMMETRY

The following points are made by Claudio D. Stern (Nature 2002 418:29):

1) How an embryo first distinguishes its left from its right side has baffled embryologists for a long time. The rotational beating of cilia -- hair-like structures attached to individual cells --is known to be essential for the process. But cilia have been seen only in mouse embryos, and it has remained unclear whether their movement could really generate the necessary molecular asymmetries.

2) Despite its superficial appearance of bilateral symmetry, the vertebrate body plan is asymmetric in several respects, most obviously in the position of internal organs such as the heart and parts of the gut. Left-right asymmetry first arises in the embryo at around the stage -- the gastrula -- when the three major cell layers of ectoderm, mesoderm and endoderm are first laid down. But until recently we knew virtually nothing about the molecular mechanisms responsible(1.2).

3) The turning point came in 1995 when four genes (Sonic hedgehog, Nodal, HNF3 and the Activin-receptor IIA) were identified as being expressed on one or the other side of the chick embryo at the gastrula stage, and their activities were implicated in heart turning(3). However, subsequent work revealed that only one of these, Nodal, is expressed asymmetrically in all vertebrates. Shortly afterwards it was discovered that a mouse mutant, called (iv) and characterized by random positioning of internal organs, carries a mutation that inactivates left-right dynein (LRD), a protein required for the beating of cilia(4). Researchers then looked for cilia in the mouse gastrula and found that the "node", a critical organizing structure in the midline of the early embryo, does indeed possess short cilia protruding from its cells, which beat in an anticlockwise circular motion and generate a leftwards flow of fluid that is strong enough to displace solid particles to the left(5). But again, the cilia could be found only in the mouse. Could different vertebrates have evolved different ways of establishing asymmetry? And could the beating of cilia really be sufficient to generate molecular asymmetry by removing a "morphogen" signal from one side of the embryo and enriching it on the other?

4) The papers by Essner et al(1) and Nonaka et al(2) answer both questions. Essner et al. reveal that cilia, as well as LRD, are indeed present in all the major vertebrate groups at appropriate stages and locations to generate left-right asymmetry. Nonaka et al. show that a flow of fluid in the reverse direction to that generated by cilia can randomize embryonic asymmetry ù and that artificially induced fluid flow is enough to control the position of the internal organs in (iv) mutant mice.

References (abridged):

1. Essner, J. J. et al. Nature 418, 37-38 (2002)

2. Nonaka, S., Shiratori, H., Saijoh, Y. & Hamada, H. Nature 418, 96-99 (2002)

3. Levin, M., Johnson, R. L., Stern, C. D., Kuehn, M. & Tabin, C. Cell 82, 803-814 (1995)

4. Supp, D. M., Witte, D. P., Potter, S. S. & Brueckner, M. Nature 389, 963-966 (1997)

5. Nonaka, S. et al. Cell 95, 829-837 (1998)

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