In mammals, precise placement of organs is essential for survival. We show here that inactivation of Roundabout (Robo) receptors 1 and 2 in mice leads to mispositioning of the stomach in the thoracic instead of the abdominal cavity, which likely contributes to poor lung inflation and lethality at birth, reminiscent of congenital diaphragmatic hernia (CDH) cases in humans. Unexpectedly, in Robo mutant mice, the primary defect preceding organ misplacement and diaphragm malformation is a delayed separation of foregut from the dorsal body wall. Foregut separation is a rarely considered morphogenetic event, and our data indicate that it occurs via repulsion of Robo-expressing foregut cells away from the Slit ligand source. In humans, genomic lesions containing Robo genes have been documented in CDH. Our findings suggest that separation of the foregut from the body wall is genetically controlled and that defects in this event may contribute to CDH.
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We thank members of the Sun and Ikeda laboratories for helpful discussions and insights and Amber Lashua and Julie Harvey for expert technical assistance. We thank Drs. David Ornitz, Brian Harfe, and Vasi Sundaresan for sharing mouse strains. E.T.D. was supported by National Science Foundation graduate research fellowship 2008044659. This work was supported by a Wright Foundation research grant and NINDS NS062047 (to L.M) and a Burroughs-Wellcome career award #1002361, American Heart grant #0950041G, March of Dimes grant 6-FY10-339, and NHLBI grant HL113870 (to X.S.).