Investigating the Origins of Congenital Heart Defects in a Mouse Model of Cornelia de Lange Syndrome

Abstract

Congenital heart defects (CHDs) are among the most common birth defects and are a major cause of infant mortality. Increasing evidence suggests that CHDs result from the combinatorial effects of variations in the expression of multiple genes throughout the genome. As one approach to understand the multifactorial origins of CHDs, we have generated and studied mouse models of Cornelia de Lange Syndrome (CdLS), a multisystem birth defects disorder that arises in most instances from haplinsufficiency for NIPBL. The NIPBL gene encodes a cohesin binding factor that is also known to have global effects on gene expression, and Nipbl‐deficient vertebrate animal models of CdLS, such as Nipbl‐deficient mice and zebrafish, recapitulate both the large array of structural birth defects observed in CdLS and the global dysregulation of gene expression observed in cells from individuals with CdLS (e.g., Kawauchi et al., 2009, PLoS Genetics; Muto et al., 2011, PLoS Biology). Strikingly, Nipbl+/− mice exhibit CHD at a frequency of ~30%, similar to the level observed in individuals with CdLS. This high degree of penetrance makes such mice an excellent model system for understanding the complex origins of CHDs.In a recent study, we generated an allelic series of Nipbl in the mouse, which allows us to selectively create or rescue Nipbl haploinsufficiency in different tissues (Santos et al., 2016, PLoS Biology). We used this allelic series to understand the tissue origins of CHD in CdLS, and found that defects were apparent from the earliest times of heart development. Specifically, we found deficits in the numbers of developing cardiac progenitor cells; defects in right ventricle development during early heart development; defects in ventricular septation during mid‐gestation; and a high incidence (~30%) of atrial septal defects (ASDs) at perinatal stages of heart development (ibid). The results of these and other studies (Chea, Calof, unpublished observations) suggested that, in CdLS, the origins of CHD lie at the earliest stages of heart development, during the initial allocation of cardiac progenitors to the first and second heart fields (FHF, SHF). Because the SHF contributes cells that make up the bulk of the right ventricle, and defects in the SHF can lead to defects in outflow tract and atrial septum development, we are particularly interested in whether Nipbl deficiency in the SHF specifically may be responsible for the CHD observed in CdLS. To test this, we are crossing mice carrying SHF‐specific Cre recombinases with NipblFlox mice, in order to generate offspring with Nipbl haploinsufficiency specifically in the SHF and its derivatives. Results from these studies will allow us to determine whether Nipbl deficiency in the SHF and its derivatives is necessary and sufficient for the development of the high incidence of CHD in CdLS.Support or Funding InformationSupported by a grant to ALC and ADL from the National Institute of Heart, Lung, and Blood Disorders (HL138659‐02) of the NIH.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.