Regulating Nipbl Gene Expression Levels in Mice Using Flip-Excision Technology to Study Heart Defects Found in Cornelia de Lange Syndrome Mice Model

Cornelia de Lange Syndrome (CdLS) is a multi-systems birth defects genetic disorder, with one of the impacted systems being the cardio-vascular system. Approximately one out of three individuals diagnosed with CdLS is born with congenital heart defects. Mutation in the Nipped-B-like (Nipbl) gene has been linked with over 60% of CdLS cases. The NIPBL protein is associated with the cohesin ring system that is necessary during sister chromatid cohesion and believed to be involved in global gene transcription. In order to help investigate the defects found in CdLS, a mouse model with reduced Nipbl expression was developed. Nipbl+/- mice demonstrate similar phenotypic characteristics observed in humans with CdLS. Particularly, Nipbl+/- mice display atrial septal defects in the heart. To effectively study the role of Nipbl during development, an enhanced Nipbl mice model was developed that takes advantage of Flip–Excision (FLEX) technology, in which the Nipbl gene can switch from mutant to wildtype conformations and vice versa, using DNA recombinases. Since the endoderm provides essential signals for proper heart development, we hypothesized that reduced levels of Nipbl in the endoderm may be responsible for the heart defects observed in Nipbl+/- mice. Therefore, we will be using Nipbl FLEX mice to manipulate levels of Nipbl expression in the endoderm to determine if proper levels of Nipbl in the endoderm are required for proper heart development. Data obtained from these experiments should provide insight to the mechanism by which heart defects develop in Nipbl+/- mice, and by extension in people with CdLS.