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Establishment of vertebrate left–right asymmetry

Key Points

  • Left–right (L/R) asymmetry provides a unique opportunity to study cellular and molecular mechanisms of asymmetry generation.

  • Symmetry breaking in the mouse might involve unidirectional fluid flow around the node, which is generated by rotational movement of the monocilia.

  • Transforming growth factor-β-related factors, Nodal and Lefty2, act as asymmetric signals. Nodal is a left-side determinant, whereas Lefty2 is an antagonist that restricts the duration and the site of Nodal action.

  • Nodal and Lefty2 might comprise a reaction–diffusion system that amplifies L/R differences. The theoretical model describes two diffusible molecules, one of which is an activator that stimulates both its own synthesis and the synthesis of its partner, which is an inhibitor. The model requires that the inhibitor diffuses more rapidly than the activator.

  • Midline structures are required to separate the left and the right halves of embryos. Lefty1 functions as a specific midline barrier.

  • A transcription factor Pitx2 mediates Nodal signals and is responsible for generating the left-side morphology of many visceral organs.

  • Although Nodal, the Lefty proteins and Pitx2 have conserved roles among vertebrates, diverse strategies might have been adopted for setting up asymmetric Nodal expression.

Abstract

The generation of morphological, such as left–right, asymmetry during development is an integral part of the establishment of a body plan. Until recently, the molecular basis of left–right asymmetry was a mystery, but studies indicate that Nodal and the Lefty proteins, transforming growth factor-β-related molecules, have a central role in generating asymmetric signals. Although the initial mechanism of symmetry breaking remains unknown, developmental biologists are beginning to analyse the pathway that leads to left–right asymmetry establishment and maintenance.

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Figure 1: Four steps of left–right asymmetric morphogenesis.
Figure 2: Genetic pathway for the determination of left–right asymmetry.
Figure 3: The node and monocilia.
Figure 4: Actions of Nodal and the Lefty proteins.
Figure 5: Asymmetric expression of Nodal, Lefty1, Lefty2 and Pitx2.
Figure 6: Transcriptional relationship between Nodal and the Lefty genes.
Figure 7: Model for the reaction–diffusion system in left–right determination.

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Acknowledgements

We thank other members of H. Hamada's lab for their stimulating discussion, S. Nonaka for recording the nodal flow shown in the supplementary information online, and S. Kondo and H. Meinhardt for their advice on the reaction–diffusion system. The work done in H. Hamada's lab was supported by CREST.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hiroshi Hamada.

Supplementary information

Related links

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DATABASES

LocusLink

ActRIIa

ActRIIb

Cryptic

Dante

Egf

Fast2

Fgf8

Gdf1

Hfh4

Hnf3-β

Ihh

Invs

Kif3a

Kif3b

Lefty1

Lefty2

Nkx2

Nkx3.2

Nodal

nt

Pitx2

Polaris

Shh

Sil

Smad2

Smad4

Smad5

Sna

Snail

OMIM

Kartagener syndrome

FURTHER INFORMATION

Chordate and vertebrate body plans

Vertebrate embryo: establishment of left–right asymmetry

Glossary

NODE

The anterior tip of the primitive streak — a structure that gives bilateral symmetry and a midline axis to the embryo. The node gives rise to anterior mesendoderm and has a function that is equivalent to the Spemann's organizer of Xenopus.

LATERAL PLATE MESODERM

(LPM). The mesoderm located in the lateral region of the early somite-stage embryo.

SITUS INVERSION

A congenital malformation in which left–right asymmetry of viscera is completely reversed.

DYNEIN

A microtubule-associated motor protein that is responsible for transporting vesicles and particles towards the proximal (minus) end of microtubules.

MONOCILIUM

A cilium that exists once per cell; each contains the nine outer microtubule doublets but lacks a central doublet. They are therefore referred to as 9+0 cilia.

SITUS DEFECT

A congenital defect in left–right asymmetry.

KINESIN

A microtubule-associated motor protein that is responsible for transporting vesicles and particles towards the distal (plus) end of microtubules.

GAP JUNCTION

A junction between two cells through which ions and small molecules can pass.

ANKYRIN

A globular protein that links spectrin, a major cytoskeletal protein, with an integral membrane protein in the erythrocyte plasma membrane. A repetitive motif of this protein — ankyrin repeat — is found in many other proteins.

CERBERUS-DAN FAMILY

A family of secreted glycoproteins with a cysteine knot that is characterized by nine conserved cysteines and a cysteine knot region. Some of these family members have anti-BMP and/or anti-Nodal activity.

PRECHORDAL PLATE

The ventral layer of the midline in a region that is rostral to the notochordal plate. It contacts the overlying neural plate at the future forebrain.

PROSPECTIVE FLOOR PLATE

The most ventral part of the neural plate that is located at the midline. It will differentiate into the floor plate and is important in specifying the ventral character of the spinal cord.

SPLANCHNOPLEURE

Dorsal layer of the lateral plate that will develop to form surface structures such as the body wall and limbs.

SOMATOPLEURE

Ventral layer of the lateral plate that will contribute to visceral organs.

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Hamada, H., Meno, C., Watanabe, D. et al. Establishment of vertebrate left–right asymmetry. Nat Rev Genet 3, 103–113 (2002). https://doi.org/10.1038/nrg732

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