Ankrd11, a chromatin regulator and a KBG syndrome risk gene, is a critical regulator of cardiac neural crest cell biology and heart development

Abstract ANKRD11 (Ankyrin Repeat Domain 11) is a chromatin regulator and a risk gene for KBG syndrome, a rare developmental disorder characterized by multiple organ abnormalities, including cardiac defects. However, the role of ANKRD11 in heart development is unknown. The neural crest plays a leading role in embryonic heart development, and its dysfunction is implicated in many congenital heart defects. Here, we demonstrate that conditional knockout of Ankrd11 in the murine embryonic neural crest leads to a severe congenital cardiac defect termed persistent truncus arteriosus (PTA), ventricular dilation, and impaired ventricular contractility. We further show these defects occur due to aberrant cardiac neural crest cell organization and failure to initiate outflow tract septation. Finally, conditional knockout of Ankrd11 in the neural crest leads to impaired Sema3C (Semaphorin 3C) expression, and reduced mTOR (mammalian target of rapamycin) and BMP (Bone Morphogenetic Protein) signaling in the cardiac neural crest cells within the outflow tract. This study identifies Ankrd11 as a novel regulator of neural crest-mediated heart development and function and suggests a mechanism for aberrant heart development in KBG syndrome patients.