Loss of Ankrd11, an epigenetic regulator and KBG syndrome risk gene, causes severe neural crest-mediated cardiac defects

Introduction. KBG syndrome is a rare developmental disorder with about 500 cases known worldwide. It is characterized by multiple organ abnormalities, including brain, craniofacial, and cardiac malformations. It is caused by deficiency of the gene ANKRD11 (Ankyrin Repeat Domain 11), an epigenetic regulator that controls histone acetylation and thereby global gene expression. Our lab previously showed that Ankrd11 regulates brain development and neural crest-mediated craniofacial development. However, its role in heart development is unknown, even though almost half of the KBG syndrome patients display heart defects, which may require open-heart surgery. Both craniofacial and heart development are notably shaped by the neural crest, an embryonic population of progenitor cells that is vital to organogenesis. KBG patients show both craniofacial and cardiac phenotypes consistent with neural crest dysregulation, making the neural crest an ideal target to study cardiac defects in a KBG model. Methods/Results. Using a mouse model with conditional knockout of Ankrd11 in the neural crest (Ankrd11ncko), we performed morphological and functional analysis of the heart and lineage tracing analysis of the cardiac neural crest. Ankrd11ncko embryos display a severe congenital heart defect called persistent truncus arteriosus, where the embryonic outflow tract fails to separate into distinct vessels, the aorta and pulmonary trunk. They also display a ventricular septal defect and a common origin of the brachiocephalic and left common carotid arteries. Micro-computed tomography (uCT) and 3D reconstruction also reveals cardiomegaly (increased heart size), and in utero echocardiography shows decreased ventricular contractility. As Ankrd11ncko embryos die at birth, this suggests a fatally defective heart function. Lineage tracing analysis during the embryonic stages of outflow tract remodeling reveals that Ankrd11ncko cardiac neural crest cells successfully populate the outflow tract but show delayed condensation and improper migration to the outflow tract endocardium, failing to fuse it at the midline and create the aorticopulmonary septum. Conclusion. We show that Ankrd11 is a novel critical regulator of heart development. Ablation of Ankrd11 in the neural crest causes severe cardiac defects, including persistent truncus arteriosus, cardiomegaly, and impaired ventricular contractility. Furthermore, Ankrd11ncko cardiac neural crest exhibits aberrant differentiation by failing to initiate the aorticopulmonary septation process. Our work contributes to our understanding of the role of epigenetic factors, like Ankrd11, in heart development, and demonstrates a mechanism for aberrant heart development in KBG syndrome patients.