Conditional Creation and Rescue of Nipbl-Deficiency in Mice Reveals Multiple Determinants of Risk for Congenital Heart Defects

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.

STAG2 cohesin is essential for heart morphogenesis

“…Consistent with this idea, our transcriptome analyses uncovered altered tissue-specific transcription patterns in Stag2 null embryonic hearts, with lower expression of cardiac genes and de-repression of genes from other lineages. Thus, we propose that defects in both proliferation and lineage specification contribute to the heart abnormalities observed in the STAG2 deficient embryos, as previously suggested in NIPBL deficient embryos or zebrafish with reduced cohesin levels ( 29, 36 ).…”

“…These findings strongly suggest that STAG2 loss results in accumulation of progenitors in the ASHF that fail to migrate into the heart tube, leading to morphological defects in ASHF derivatives such as the right ventricle and the OFT. Defects in migration of progenitors has been suggested as the cause of heart defects in murine embryos and zebrafish deficient for the cohesin loader NIPBL ( 28, 29 ).…”

The Hole and the Whole: Lessons from Manipulation of Nipbl Deficiency

“…In the fascinating research study described in this issue of PLOS Biology , Rosaysela Santos and her colleagues took a novel approach to understanding CHDs observed in a single-gene trait, Cornelia de Lange syndrome (CdLS), using a sophisticated conditional allele in mice [ 8 ]. In so doing, they made novel observations that add further complexity to the way in which we need to think about CHD pathogenesis.…”

“…In Santos et al [ 8 ], the research team used a targeted trapping allele, Flip-Excision (FlEx) [ 16 ], in Nipbl . The flexibility engineered into this technology allowed them to conditionally knock out Nipbl , similar to a more typical Cre-Lox strategy, but also to conditionally express wild-type Nipbl at physiologic levels in the context of a global Nipbl knock-out.…”

“…Next, the authors used the same Cre drivers to explore whether conditional expression of Nipbl on the global Nipbl knock out background rescued the ASD [ 8 ]. Here, the fireworks begin (it is July 4 as I write this, so why not!).…”