Notch signaling regulates left–right asymmetry determination by inducing Nodal expression

  1. Luke T. Krebs1,4,
  2. Naomi Iwai2,3,4,
  3. Shigenori Nonaka2,3,
  4. Ian C. Welsh1,
  5. Yu Lan1,5,
  6. Rulang Jiang1,5,
  7. Yukio Saijoh2,
  8. Timothy P. O'Brien1,
  9. Hiroshi Hamada2,3,6, and
  10. Thomas Gridley1,7
  1. 1The Jackson Laboratory, Bar Harbor, Maine 04609, USA; 2Developmental Genetics Group, Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan; 3CREST (Core Research for Evolutional Science and Technology), Japan Science and Technology Corporation (JST), Osaka 565-0871, Japan

Abstract

Generation of left–right asymmetry is an integral part of the establishment of the vertebrate body plan. Here we show that the Notch signaling pathway plays a primary role in the establishment of left–right asymmetry in mice by directly regulating expression of the Nodal gene. Embryos mutant for the Notch ligand Dll1 or doubly mutant for the Notch1 and Notch2 receptors exhibit multiple defects in left–right asymmetry. Analysis of the enhancer regulating node-specific Nodal expression revealed the presence of binding sites for the RBP-J protein, the primary transcriptional mediator of Notch signaling. Mutation of these sites destroyed the ability of this enhancer to direct node-specific gene expression in transgenic mice. Our results demonstrate that Dll1-mediated Notch signaling is essential for generation of left–right asymmetry, and that the Notch pathway acts upstream ofNodal expression during left–right asymmetry determination in mice.

Keywords

Footnotes

  • ↵4 These authors contributed equally to this work.

  • ↵5 Present address: Center for Oral Biology, University of Rochester,

  • ↵6 E-MAIL ; FAX 81-6-6878-9846.

  • ↵7 E-MAIL ; FAX (207) 288-6077.

  • School of Medicine and Dentistry, Rochester, NY 14642, USA.

  • Corresponding authors.

  • Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/doi/10.1101/gad.1084703.

    • Received February 13, 2003.
    • Accepted March 26, 2003.
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  1. Published in Advance May 2, 2003, doi: 10.1101/gad.1084703 Genes & Dev. 17: 1207-1212 Cold Spring Harbor Laboratory Press

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