Inhibition of TGFβ pathway prevents short body size and cardiac defects in Nipbl-deficient mice, a mouse model of Cornelia de Lange syndrome

Abstract

AbstractCornelia de Lange is a rare developmental disorder affecting the formation of many organs following a delay in developmental processes. The disease mainly caused by mutation of the cohesin loader NIPBL is left without any therapeutic strategy. Besides, a short body size and neurological defects, more than half of CdL children feature various cardiac malformations.To mimic the cardiac defects and test a therapeutic preventive strategy, we generated a C57Bl/6 nipbl+/- mouse model of the disease. These mice featured a severe delay in embryonic and postnatal growth.The nipbl-deficient embryonic and neonatal hearts developed ventricular hypertrophy, aortic and valve defects associated with a persistent truncus arteriosus and a ventricular septal defect. The adult hearts then featured a severe aortic senescence phenotype and a stenosis resulting in an increase in aortic flux velocity and persistent left ventricular hypertrophy. Using proteomics and RNA-sequencing in embryos, we identified a dysregulated TGFβ pathway in the outflow tract of embryonic hearts as well as the presence of senescent cells as early as in E13.5 nipbl+/- embryonic hearts. Treatment of pregnant nipbl+/- mice with a TGβR (ALK5) inhibitor from E9.5 to E13.5 rescued the cardiac phenotype as well as the body size of mice at birth.Altogether our data revealed that an exacerbated TFGβ pathway associated with cell senescence is at the origin of many defects in a CdL mouse model. This druggable pathway opens the path toward a potential preventive therapeutic strategy for CdL patients.