Abstract
Elucidating the causes of congenital heart defects is made difficult by the complex morphogenesis of the mammalian heart, which takes place early in development, involves contributions from multiple germ layers, and is controlled by many genes. Here, we use a conditional/invertible genetic strategy to identify the cell lineage(s) responsible for the development of heart defects in a Nipbl-deficient mouse model of Cornelia de Lange Syndrome, in which global yet subtle transcriptional dysregulation leads to development of atrial septal defects (ASDs) at high frequency. Using an approach that allows for recombinase-mediated creation or rescue of Nipbl deficiency in different lineages, we uncover complex interactions between the cardiac mesoderm, endoderm, and the rest of the embryo, whereby the risk conferred by genetic abnormality in any one lineage is modified, in a surprisingly non-additive way, by the status of others. We argue that these results are best understood in the context of a model in which the risk of heart defects is associated with the adequacy of early progenitor cell populations relative to the sizes of the structures they must eventually form.
Highlights
Congenital heart defects (CHDs) are the most common of human birth defects, and a leading cause of perinatal morbidity and mortality [1]
We studied atrial septal defects in a mouse model of Cornelia de Lange Syndrome, in which loss of one copy of the Nipped-B homologue (Nipbl) gene produces frequent developmental abnormalities
Because many of the nearly 100 genes that have been linked to the production of cardiac septal defects [34,35] influence heart development through actions at early embryonic stages, long before cardiac septa form, we examined heart development in Nipbl+/- mice at successively earlier developmental stages to determine whether earlier structural abnormalities could be found
Summary
Congenital heart defects, the most common birth defect, are thought mainly to arise through interactions among multiple genes. Being Nipbl-deficient in the rest of the body reduced the risk conferred by being Nipbl-deficient in either of two distinct cardiogenic lineages We hypothesize that this effect is driven by developmental coupling between body size and heart size, with defects arising when progenitor cells cannot be provided fast enough to meet the requirements imposed on the heart by other growing tissues. To our knowledge, this is the first genetic demonstration that major risk factors for heart defects are likely to lie outside of the heart itself
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