Developing Symmetry and Asymmetry

Science's STKE  17 May 2005:
Vol. 2005, Issue 284, pp. tw185
DOI: 10.1126/stke.2842005tw185

Recent studies in several species have revealed that, rather than being the default condition, the symmetrical and synchronized development of somites on both sides of the vertebrate embryo depends on overcoming signals that promote asymmetry. Some vertebrate structures, like the skeleton, develop with bilateral symmetry, whereas others, like the heart or the stomach, develop asymmetrically. Somites, which give rise to symmetric structures, such as the vertebrae, ribs, and skeletal musculature of the trunk, arise in bilaterally symmetric pairs in an anterior to posterior sequence (see Hornstein and Tabin). Kawakami et al. found that blocking retinoic acid (RA) production in zebrafish resulted in biased asymmetry of somite development, unless H+/K+ ATPase activity or lrd (left-right dynein) translation (both critical to development of bilateral asymmetry) was inhibited. Inhibition of H+/K+ ATPase or Notch activity, or down-regulation of lrd translation, led to random asymmetry in somitogenesis, suggesting that RA signaling may become lateralized in response to the normal cues for asymmetry. Vermot and Porquié, from a research group that recently showed that mice lacking the RA synthetic enzyme RALDH2 (retinaldehyde-specific dehydrogenase type 2) displayed biased asymmetric somite development (see related Science article by Vermot et al.), found that inhibiting RA production in cultured chick embryos led to biased asymmetric somite development as well. When beads containing Sonic hedgehog (Shh) were implanted to reverse left-right asymmetry, the asymmetric bias in somitogenesis was reversed as well. A similar reversal in the asymmetric bias in somitogenesis was observed in mice when a mutation that permitted left-right asymmetry to be reversed was combined with deletion of Raldh2. Thus, in all three species, RA signaling blocks asymmetric somitogenesis in response to the signals that lead to the asymmetric development of internal organs.

In mice, the initial loss of symmetry involves leftward fluid flow generated by ciliary movement in a midline region called the node. Using time-lapse imaging of embryos at the one- to three-somite stage, in which membrane lipids were stained with a fluorescent dye and the node was visualized by confocal microscopy, Tanaka et al. observed 0.3 to 5 μm lipophilic membrane-sheathed objects moving leftward across the node. The release from microvilli and movement of these nodal vesicular particles (NVPs) was inhibited when fibroblast growth factor (FGF) signaling was blocked. Immunohistochemistry indicated that Shh and RA were associated with NVPs; moreover, Shh and RA could restore NVP flow when FGF signaling was inhibited. Thus, the authors proposed that NVPs launched by FGF act as ferries to transport morphogens like Shh and RA across the node.

Y. Kawakami, Á. Raya, R. M. Raya, C. Rodríguez-Esteban, J. C. Izpisúa Belmonte, Retinoic acid signalling links left-right asymmetric patterning and bilaterally symmetric somitogenesis in the zebrafish embryo. Nature 435, 165-171 (2005). [PubMed]

J. Vermot, O. Porquié, Retinoic acid coordinates somitogenesis and left-right patterning in vertebrate embryos. Nature 435, 215-220 (2005). [PubMed]

Y. Tanaka, Y. Okada, N. Hirokawa, FGF-induced vesicular release of Sonic hedgehog and retinoic acid in leftward nodal flow is critical for left-right determination. Nature 435, 172-177 (2005). [PubMed]

E. Hornstein, C. J. Tabin, Asymmetrical threat averted. Nature 435, 155-156 (2005). [PubMed]