Brief reviews
Left-Right Determination

https://doi.org/10.1016/S1050-1738(00)00064-5Get rights and content

Abstract

Recent advances have given us new insights into the molecular basis of organ position. A gene cascade that determines left-right positioning of organ primordia has emerged. In here we present the current knowledge of the molecular determinants of organ positioning during vertebrate embryogenesis.

Section snippets

Organizing Structures

The term node defines the mammalian structure that is homologous to Hensen's node in avians and Spemann's organizer in amphibians. This homology includes its embryological origin, its ability to induce axial specification of the body plan and its profile of gene expression Beddington 1994, Izpisua-Belmonte et al. 1993. Recent reports support a key role for the node in the initial specification of the left and right sides of the body. In chick, morphological asymmetry of Hensen's node is the

Signals to Organ Primordia

The earliest molecular asymmetries in the mouse occur after the establishment of nodal flow with the appearance of the TGF-β superfamily members nodal and Lefty-1 on the left side adjacent to the node Lowe et al. 1996, Meno et al. 1996. Aberrant patterns of nodal expression correlate with situs abnormalities and missexpression of nodal on the right side of the embryo results in randomized situs Levin et al. 1995, Lohr et al. 1997, Lowe et al. 1996, Ryan et al. 1998. In the chick, nodal

Human Genetics of Laterality

Autosomal dominant, autosomal recessive, and X-linked inheritance patterns have been described for syndromic human situs abnormalities. However, our knowledge of these defects is largely limited to the clinical evaluation of familial cases. Several known genes in the L/R signaling cascade have been cloned in humans, often as a result of mapping candidate genes for diverse syndromes.

Kartagener's syndrome is an inherited disease characterized by the clinical triad of bronchiectasis, sinusitis,

Conclusion

In the last years significant progress has been made in terms of identifying the individual molecular components necessary for determining left-right patterning decisions and their position within the signaling cascade hierarchy. In chick, an activin or activin-related molecule appears to be critical for initiation of asymmetric gene expression in the vicinity of the node. In mice, “nodal flow” breaks the initial bilateral symmetry and signals the onset of a molecular cascade of asymmetric gene

Acknowledgements

We thank Dr. Brian Cooper for critical reading of the manuscript. P.R.-L. is a recipient of AHA Western States Affiliate Beginning Grant-in-Aid. A.K.R. is a recipient of the Burroughs Wellcome Fund Career Award.

References (56)

  • C Meno et al.

    lefty-1 is required for left-right determination as a regular of lefty-2 and nodal

    Cell

    (1998)
  • S Nonaka et al.

    Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein

    Cell

    (1998)
  • Y Okada et al.

    Abnormal nodal flow precedes situs inversus in iv and inv mice

    Mol Cell

    (1999)
  • M.E Piedra et al.

    Pitx2 participates in the late phase of the pathway controlling left-right asymmetry

    Cell

    (1998)
  • Y Yokouchi et al.

    Antagonistic signaling by Caronte, a novel Cerberus-related gene, establishes left-right asymmetric gene expression

    Cell

    (1999)
  • H Yoshioka et al.

    Pitx2, a bicoid-type homeobox gene, is involved in a lefty-signaling pathway in determination of left-right asymmetry

    Cell

    (1998)
  • R.S Beddington

    Induction of a second neural axis by the mouse node

    Development

    (1994)
  • E Belloni et al.

    Identification of Sonic hedgehog as a candidate gene responsible for holoprosencephaly

    Nat Genet

    (1996)
  • M.J Benedyk et al.

    Odd-paireda zinc finger pair-rule protein required for the timely activation of engrailed and wingless in Drosophila embryos

    Genes Dev

    (1994)
  • Brown NA, Anderson RH: 1999. Symmetry and laterality in the human heart: developmental implications. In Harvey R,...
  • H Chang et al.

    Smad5 knockout mice die at mid-gestation due to multiple embryonic and extraembryonic defects

    Development

    (1999)
  • C Chazaud et al.

    Retinoic acid is required in the mouse embryo for left-right asymmetry determination and heart morphogenesis

    Development

    (1999)
  • J Chen et al.

    Mutation of the mouse hepatocyte nuclear factor/forkhead homologue 4 gene results in an absence of cilia and random left-right asymmetry

    J Clin Invest

    (1998)
  • F.L Conlon et al.

    A primary requirement for nodal in the formation and maintenance of the primitive streak in the mouse

    Development

    (1994)
  • J Cooke

    Vertebrate embryo handedness

    Nature

    (1995)
  • P.J Gage et al.

    Dosage requirement of Pitx2 for development of multiple organs

    Development

    (1999)
  • M Gebbia et al.

    X-linked situs abnormalities result from mutations in ZIC3

    Nat Genet

    (1997)
  • R Gershoni-Baruch et al.

    Immotilie cilia syndrome including polysplenia, situs inversus, and extrahepatic biliary artesia

    Am J Med Genet

    (1989)
  • Cited by (4)

    © 2001, Elsevier Science Inc. All rights reserved. 1050-1738/01/$-see front matter

    View full text