Notch signaling regulates left-right asymmetry determination by inducing Nodal expression.
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 of Nodal expression during left-right asymmetry determination in mice.
The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
Luke T
LT
Krebs
Naomi
N
Iwai
Shigenori
S
Nonaka
Ian C
IC
Welsh
Yu
Y
Lan
Rulang
R
Jiang
Yukio
Y
Saijoh
Timothy P
TP
O'Brien
Hiroshi
H
Hamada
Thomas
T
Gridley
D000818:Animals; D001665:Binding Sites; D019521:Body Patterning / Q000502:physiology*; D002923:Cilia / Q000235:genetics / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D055458:Left-Right Determination Factors; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D009154:Mutation; D055457:Nodal Protein; D051880:Receptors, Notch; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism
D047908:Intracellular Signaling Peptides and Proteins; D055458:Left-Right Determination Factors; D008565:Membrane Proteins; D055457:Nodal Protein; C526008:Nodal protein, mouse; D051880:Receptors, Notch; D016212:Transforming Growth Factor beta; C064045:delta protein