International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


Oral Presentation

Tuesday 19 November

09:45 - 10:00 HRS

NOTCH SIGNALING REGULATES LEFT-RIGHT DETERMINATION IN MICE

T. Gridley
Jackson Laboratory

Co-Authors: Krebs LT, Welsh IC, O'Brien TP
Institutions: Jackson Laboratory

The Notch signaling pathway is evolutionarily conserved and is critically involved in the development of species as diverse as nematodes and mammals. Here we show that the Notch signaling pathway regulates left-right determination during mouse development. Heart looping and axial rotation are the first morphological indicators of left-right determination. Disruption of the Dll1 gene, which encodes a ligand for Notch family receptors, results in defects in left-right determination. Both heart looping and axial rotation are randomized in Dll1 mutant embryos. We examined embryos mutant for each of the four Notch family receptors for defects in heart looping and axial rotation. We did not detect any laterality defects in the single receptor mutants, but Notch1/Notch2 double homozygous mutants did exhibit laterality defects at low penetrance. This suggests that functional redundancy exists among the Notch receptors during left-right axis determination. Analysis of Dll1 mutants revealed perturbed expression of markers for the left-right axis. Nodal and Lefty2 were not expressed in the left lateral plate mesoderm (LLPM) in Dll1 homozygous mutants, while Pitx2 expression in the LLPM was randomized. Our results suggest that the Notch signaling pathway acts upstream of the Nodal gene in the cascade of genetic interactions responsible for left-right axis determination in mice. Experiments are currently underway to determine the mechanism for Notch regulation of left-right determination.


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