Cardiovascular defects associated with abnormalities in midline development in the Loop-tail mouse mutant

Loop-tail (Lp) is a naturally occurring mouse mutant that develops severe n eural tube defects. In this study, we describe complex cardiovascular defec ts in Lp homozygotes, which include double-outlet right ventricle, with obl igatory perimembranous ventricular septal defects, and double-sided aortic arch, with associated abnormalities in the aortic arch arteries. Outflow tr act and aortic arch defects are often related to abnormalities in the cardi ac neural crest, but using molecular and anatomic markers, we show that neu ral crest migration is normal in Lp/Lp embryos. On the other hand, the hear t fails to loop normally in Lp/Lp embryos, in association with incomplete a xial rotation and reduced cervical flexion. As a consequence, the ventricul ar loop is shifted posteromedially relative to its position in wild-type em bryos. This suggests that the observed cardiac alignment defects in the Lp mutant may be secondary to failure of neural tube closure and incomplete ax ial rotation. Double-sided aortic arch is a rare finding among mouse models . In humans, it is usuary an isolated malformation, only rarely occurring i n combination with other cardiac defects. We suggest that the double-sided arch arises as a primary defect in the Lp mutant, unrelated to the alignmen t defects, perhaps reflecting a role for the las-yet-unknown) Lp gene in ma intenance/regression of the aortic arch system.