Developmental biology

Asymmetry with a twist

In snails, manipulating the orientation of cells in the early embryo alters the left–right asymmetry of the shell and body. These findings refine the search for the symmetry-breaking event in this and other animals.

The elegant shape of seashells has long fascinated us, and their beautiful curved forms have inspired many man-made designs. The spiral shapes can be divided into two distinct groups on the basis of the direction of coiling. Hold a shell so that you look down onto the pointed end, and you will see that most shells spiral downward in a clockwise direction (Fig. 1); only a few twist in the opposite direction. This property of shell coiling is termed chirality; shells with clockwise spirals are called dextral shells, and those with anticlockwise spirals are termed sinistral shells.

Figure 1: Spiralling downward.
figure1

N. H. PATEL

Most shells, like that of the sea snail Architectonica perspectiva shown here, spiral downward in a clockwise manner and are termed dextral shells. Shells with anticlockwise spirals are called sinistral shells.

These differences in chirality are a manifestation of left–right asymmetry of the organs of the animal. In the case of the shell, the gland that makes this structure is producing shell material at different rates on the left and right sides, leading to the coiling pattern as the shell grows. Through a conceptually simple, although technically challenging, study in the snail, Kuroda and colleagues1 show (page 790 of this issue) that they can reverse the chirality of the shell, and the asymmetry of other organs, by mechanically altering the relative orientation of cells in the early embryo.

Kuroda et al.1 worked with a pond snail, Lymnaea stagnalis. Whereas most species of snail have dextral shells, and a few have sinistral shells, L. stagnalis falls into a relatively rare group in which both chiralities exist within the same population. The difference between dextral and sinistral individuals can be detected during the first few cell divisions of the embryo — as the four-cell embryo undergoes cleavage to become an eight-cell embryo. For dextral snail embryos, the smaller daughter cells at the four-to-eight-cell transition twist clockwise as cell division occurs. In the case of sinistral snail embryos, the daughter cells are initially directly on top of their division partners, but then twist anticlockwise (Fig. 2). The result is that dextral and sinistral embryos look like mirror images of each other at the eight-cell stage, just as their shells will look like mirror images of each other as adults.

Figure 2: Reversing asymmetry in snails.
figure2

At the transition from the four- to eight-cell stage in the embryo of the pond snail, Lymnaea stagnalis, newly formed smaller daughter cells twist either clockwise or anticlockwise. This chirality (direction of twisting) correlates with the chirality of the adult shell and the left–right asymmetry of other body organs. For sinistral snail embryos, the smaller daughter cells twist anticlockwise after cell division (sinistral cleavage; blue arrows). For dextral snail embryos, the daughter cells twist clockwise as cell division occurs (dextral cleavage; red arrows). Kuroda et al.1 used glass rods to push on the cells at the eight-cell stage, forcing them into the opposite orientation. The result was a reversal of chirality of the individual that developed from the manipulated embryo. Embryos that started with a sinistral cleavage, but were forced into a dextral orientation, grew into adults with dextral shells, whereas embryos that started with a dextral cleavage pattern, but were forced into a sinistral orientation, developed into adults with sinistral shells.

Thanks to the outstanding work of 'gentle-man' scientists of the 1920s and 1930s, we also understand the genetics of snail chirality. Professor Arthur Boycott of the University of London recruited a team of naturalists, most notably Captain Cyril Diver, a part-time parliamentary administrator, to examine the genetics of chirality in Lymnaea peregra, a close relative of L. stagnalis. What they described2 was the founding example of the phenomenon we now call maternal-effect inheritance3. Simply put, it is not the genotype of the individual animal that determines a particular phenotype (in this case the dextral or sinistral shell); rather, it is the genotype of the mother that determines the phenotype of her progeny. In the case of both Lymnaea species, a single genetic locus controls chirality, with the dextral allele acting in a dominant manner. If we think of the two alleles of the chirality locus as D and d, then mothers who are DD or Dd give rise to dextral progeny, whereas dd mothers give rise to sinistral progeny. The genotype of the father has no bearing on the phenotype of the offspring.

Thus, Kuroda et al. started with DD or Dd mothers, knowing that all their progeny would exhibit a dextral cleavage pattern and normally form dextral shells, and with dd mothers, whose embryos would display a sinistral cleavage pattern and form sinistral shells. By using small glass rods to push on the cells, the authors could change the cleavage pattern of the embryos. They took embryos that should have cleaved dextrally, and forced the cells at the eight-cell stage to take on the orientation normally seen for sinistral embryos, and vice versa (Fig. 2). Remarkably, this reversed the chirality of the animals as they grew into adults. So, merely changing the relative orientation of the cells at the eight-cell stage can completely override the maternal-effect specification of chirality. Before these experiments1, it was conceivable that the chirality of the cell-cleavage pattern and that of the shell and organs later on were correlated, but did not represent cause and effect. Now we know that the maternal chirality locus controls the orientation of the cells at the eight-cell stage, and that this orientation ultimately controls the adult snail's chirality.

Kuroda and colleagues' findings1 suggest that it is the pattern of cell–cell interactions initiated at the eight-cell stage that dictates shell chirality, and that these interactions differ depending on the cleavage pattern. We still do not know what the maternal chirality locus encodes, but the gene product in some way regulates the cellular cytoskeleton and thus dictates the orientation of cell division and of cells at the eight-cell stage. We also do not know the nature of the subsequent cellular interactions, but we might glean some clues from studies of the nematode worm Caenorhabditis elegans. Similar mechanical manipulations were used to show that specific cell–cell interactions establish left–right asymmetry in C. elegans4, and genetic screens5 have now revealed some of the molecules involved in this process.

Of course, this type of left–right asymmetry is not confined to snails and nematodes. For example, humans and other vertebrates have striking asymmetries in the placement of organs such as the heart, lungs, liver and gut. Recent work6 has shown that the genes used to control left–right asymmetry in snails and vertebrates share certain features. Specifically, the genes encoding the signalling molecule Nodal and the transcription factor Pitx, both of which have well-studied roles in vertebrate left–right asymmetry, are asymmetrically expressed (only on the right side in dextral species and only on the left side in sinistral species), and are functionally involved in determining left–right asymmetry of snails starting at about the 32–64-cell stage6. Indeed, the mechanical manipulations of Kuroda et al.1 also reversed the left–right expression of these two genes.

Thus, studying snail left–right asymmetry will be relevant to understanding the phenomenon in vertebrates as well. In mice, the symmetry-breaking event seems to involve an asymmetry in extraembryonic-fluid flow set up by cilia7, whereas in chickens, it seems instead to involve early embryonic cell migration8. Snail embryos do not have cilia at the eight-cell stage, so it is difficult to predict how the maternally controlled symmetry-breaking process in snails relates to the early events in vertebrates. The final twist to this tale is yet to be told.

References

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    Grande, C. & Patel, N. H. Nature 457, 1007–1011 (2009).

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Patel, N. Asymmetry with a twist. Nature 462, 727–728 (2009). https://doi.org/10.1038/462727a

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