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(Circulation Research. 2001;89:6.)
© 2001 American Heart Association, Inc.

Molecular Medicine

Cardiovascular Defects Associated With Abnormalities in Midline Development in the Loop-tail Mouse Mutant

Deborah J. Henderson¹, Simon J. Conway¹, Nicholas D. E. Greene¹, Dianne Gerrelli, Jennifer N. Murdoch, Robert H. Anderson, Andrew J. Copp

From the Neural Development Unit (D.J.H., N.D.E.G., D.G., J.N.M., A.J.C.), Institute of Child Health, University College London, London UK; the Institute of Molecular Medicine and Genetics (S.J.C.), Medical College of Georgia, Augusta; and the Cardiology Unit (R.H.A.), Great Ormond Street Hospital for Children, London, UK.

Correspondence to Dr Deborah J. Henderson, Neural Development Unit, Institute of Child Health, University College London, 30 Guilford St, London WC1N 1EH UK. E-mail dhender{at}ich.ucl.ac.uk

Abstract

Abstract—Loop-tail (Lp) is a naturally occurring mouse mutant that develops severe neural tube defects. In this study, we describe complex cardiovascular defects in Lp homozygotes, which include double-outlet right ventricle, with obligatory perimembranous ventricular septal defects, and double-sided aortic arch, with associated abnormalities in the aortic arch arteries. Outflow tract and aortic arch defects are often related to abnormalities in the cardiac neural crest, but using molecular and anatomic markers, we show that neural crest migration is normal in Lp/Lp embryos. On the other hand, the heart fails to loop normally in Lp/Lp embryos, in association with incomplete axial rotation and reduced cervical flexion. As a consequence, the ventricular loop is shifted posteromedially relative to its position in wild-type embryos. This suggests that the observed cardiac alignment defects in the Lp mutant may be secondary to failure of neural tube closure and incomplete axial rotation. Double-sided aortic arch is a rare finding among mouse models. In humans, it is usually an isolated malformation, only rarely occurring in combination with other cardiac defects. We suggest that the double-sided arch arises as a primary defect in the Lp mutant, unrelated to the alignment defects, perhaps reflecting a role for the (as-yet-unknown) Lp gene in maintenance/regression of the aortic arch system.

Key Words: congenital heart defects • mouse mutants • double-outlet right ventricle • double-sided aortic arch • midline defects

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