The somites are embryonic elements that give rise to the muscles, skeleton and some skin layers of the trunk. They form in a symmetrical fashion, but to do so they must be shielded from asymmetrical cues.
The human body looks deceptively symmetrical from the outside. In contrast to this external symmetry, our internal organs are in an asymmetrical, yet reproducible, arrangement. The heart is on the left and the lung next to it is smaller than that on the right. Within the abdominal cavity, the intestines form a clockwise loop; the stomach, pancreas and spleen are on the left, whereas the liver and gall bladder are on the right. But our body plan does not start out this way, and some body parts — the somites, for instance — must remain bilaterally symmetrical. A striking series of findings by Kawakami et al.1 and Vermot and Pourquié2, published on pages 165 and 215 of this issue, along with a complementary manuscript in Science3, teach us how somite formation proceeds in a bilaterally synchronized fashion (Fig. 1). Furthermore, Kawakami et al. and Tanaka et al.4, also writing in this issue (page 172), shed new light on how asymmetry, which is necessary for the physiological function of many organs, is first established in the embryo (Box 1).
The left–right differences seen in many of our internal organs are rooted in a cascade of molecular asymmetries that is established during development (Box 1). Discoveries over the past decade have provided an increasingly detailed picture of how such left–right asymmetry is imposed on the developing embryo5. However, regulation of the alternative — bilaterally symmetrical morphogenesis — has not been given serious attention.
As the embryo begins symmetrically, it is perhaps natural that researchers have intuitively viewed symmetry as a default state. For instance, this view has been applied to the somites, which give rise to tissues of the body wall, such as the musculature, skeleton and some skin layers. Somites are generated bilaterally in symmetrical pairs, with one somite of each pair on each side of the developing spinal cord. This process is driven by bilaterally symmetrical waves of gene expression6. The first pair of somites emerges at the anterior part of the embryo (next to the head), and more caudal pairs of somites form successively in an anterior–posterior sequence.
Kawakami et al.1, Vermot and Pourquié2 and Vermot et al.3 now show that somite formation can proceed in a bilaterally synchronized fashion only because somites are actively masked from information that would otherwise cause them to develop asymmetrically. Experiments in mammals, birds and fish all yield clues that somites are masked from left–right cues, and so are held in symmetrical register, by a signal that depends on retinoic acid (RA). When RA activity is experimentally attenuated, bilateral segmentation is taken out of phase.
This symmetry-generating mechanism is necessary because, to develop properly, somites need to be refractory to left–right signals that are present in their physical territory. In principle, somite cells could simply ‘ignore’ such cues by not expressing the receptive components needed to interpret them (if, for instance, they did not produce receptors for the relevant growth factors). But what profoundly complicates things is that the very same left–right signalling cues are used to pattern somites along the anterior–posterior axis.
This problem of common signals being put to conflicting use finds its origin in a key principle that has emerged in modern molecular embryology. A surprisingly small number of molecular signals — such as Wnt, Notch, Hedgehogs, bone morphogenetic proteins and fibroblast growth factors (FGFs) — are repeatedly employed in different developmental settings, often in conjunction with distinct cofactors, to orchestrate differentiation and patterning. As in the composition of a musical piece, biological motifs are used over and over again, with changes of context and emphasis to generate new interpretations.
The anterior–posterior patterning of somites, for instance, is specified by the combined action of the Notch, Wnt, FGF8 and RA signalling pathways6. At the same time, the Notch, FGF8 and RA pathways are also instrumental in left–right determination5. This conflict makes it necessary to block the effect of side-specific signalling, to hold somitogenesis in synchronized and symmetrical register. That need is met, the new papers show1,2,3, by an RA-dependent mechanism. More broadly, these new findings suggest that conflicting developmental pathways in general may be intermingled in a harmonious way through buffering mechanisms.
We have a lot to learn yet about such buffering mechanisms. In this particular case, it is still unclear exactly how RA mediates the masking of left–right signals. Might this molecule be differentially spread in the left and right somitic fields? On the basis of the expression patterns of messenger RNAs encoding RA-metabolizing enzymes, Kawakami et al.1 suggest that the answer is no. However, a relevant enzyme might still be differentially regulated at a post-transcriptional level.
Another question concerns the relevant molecular targets of RA. RA is known to antagonize FGF8, which is generated at the posterior end of the embryo during somitogenesis. This antagonism is crucial for segmentation to proceed6, but it would be interesting to investigate whether the FGF8–RA interface also serves a role in buffering left–right signalling. An alternative protein that might buffer the system is Lefty-1, which is an important inhibitor of side-biasing information flow, although it acts at a stage downstream from the factors that impinge directly on the somites. Consistent with this possibility, the production of Lefty-1 is induced by RA and occurs in the midline of the embryo.
The new studies1,2,3 might also have clinical relevance. RA is produced from vitamin A in the body, so a maternal shortage of vitamin A during pregnancy might be associated with increased rates of fetal skeletal defects, such as hemivertebrae and scoliosis. The World Health Organization has found vitamin-A deficiency to be common in south Asia and Africa, suggesting that millions of pregnancies a year are carried by women with a vitamin-A shortage7. This astonishing number of pregnancies at potential risk might promote epidemiological studies of this theoretical correlation.
Kawakami, Y., Raya, Á., Raya, R. M., Rodríguez-Esteban, C. & Izpisúa Belmonte, J. C. Nature 435, 165–171 (2005).
Vermot, J. & Pourquié, O. Nature 435, 215–220 (2005).
Vermot, J. et al. Science doi:10.1126/science.1108363 (2005).
Tanaka, Y., Okada, Y. & Hirokawa, N. Nature 435, 172–177 (2005).
Levin, M. Mech. Dev. 122, 3–25 (2005).
Pourquié, O. Int. J. Dev. Biol. 47, 597–603 (2003).
Zhang, X. M., Ramalho-Santos, M. & McMahon, A. P. Cell 105, 781–792 (2001).
Essner, J. J. et al. Development 132, 1247–1260 (2005).
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