Abstract
BackgroundCongenital heart defects are the leading non-infectious cause of death in children. Genetic studies in the mouse have been crucial to uncover new genes and signaling pathways associated with heart development and congenital heart disease. The identification of murine models of congenital cardiac malformations in high-throughput mutagenesis screens and in gene-targeted models is hindered by the opacity of the mouse embryo.ResultsWe developed and optimized a novel method for high-throughput multi-embryo magnetic resonance imaging (MRI). Using this approach we identified cardiac malformations in phosphatidylserine receptor (Ptdsr) deficient embryos. These included ventricular septal defects, double-outlet right ventricle, and hypoplasia of the pulmonary artery and thymus. These results indicate that Ptdsr plays a key role in cardiac development.ConclusionsOur novel multi-embryo MRI technique enables high-throughput identification of murine models for human congenital cardiopulmonary malformations at high spatial resolution. The technique can be easily adapted for mouse mutagenesis screens and, thus provides an important new tool for identifying new mouse models for human congenital heart diseases.
Highlights
Congenital heart defects are the leading non-infectious cause of death in children
The technique can be adapted for mouse mutagenesis screens and, provides an important new tool for identifying new mouse models for human congenital heart diseases
Cardiac malformations in mice lacking phosphatidylserine receptor (Ptdsr) We evaluated the role of multi-embryo magnetic resonance imaging (MRI) in analyzing unexplained lethality in embryos generated in collaborating laboratories
Summary
Congenital heart defects are the leading non-infectious cause of death in children. Genetic studies in the mouse have been crucial to uncover new genes and signaling pathways associated with heart development and congenital heart disease. Human genetic studies have identified some genes that cause congenital cardiac malformations, the molecular and developmental mechanisms underlying most of these defects remain largely unknown. High-throughput cardiovascular genomic approaches in the mouse have been hampered by the paucity of phenotyping tools that allow efficient identification of complex cardiac malformations. New technological approaches must be harnessed that allow an efficient phenotyping of heart defects and of subtle cardiac abnormalities that are at danger of being overseen in traditional histopathology screens. This is even more important in the light of upcoming new endeavors in functional mouse genome annotation [10]. The success of genome wide saturation mutagenesis screens depends on improved phenotyping, and new high-resolution imaging approaches for mouse mutants are one of the most important which need to be established
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