Funding outcome

Heart defects are the most common type of birth defect and are linked to abnormal brain development. Yet, the mechanism of this influence is unclear. Heart defects are often caused by improper development of the neural crest, a multipurpose embryonic tissue that shapes many organs during development, including the heart. Children with KBG syndrome, a rare neurodevelopmental disorder, display both heart defects that often require surgery, and brain malformations that lead to intellectual disability, learning difficulties and abnormal behaviour. KBG syndrome is caused by a mutation in a little-studied gene called Ankrd11, which regulates neural crest cell function during embryonic organogenesis. However, its role in neural crest-assisted heart development is unknown. My initial data indicate that deletion of Ankrd11 in the neural crest in a mouse model results in a severely enlarged heart with reduced contractility and blood flow. Importantly, brain development is sensitive to changing oxygen levels. If defective heart function changes blood flow to the brain, it may permanently impact neural development. Here, I will investigate how the deficiency of Ankrd11 in the neural crest in a mouse model impairs heart development, and if the consequent blood flow defect causes deficits in brain development. The results of this project will show how Ankrd11 directs heart development through neural crest regulation, discover how heart defects can affect fetal brain formation, and offer better counselling for KBG patients and their families. I hope the results from this project will inspire novel therapies for patients with KBG syndrome and congenital heart malformations at large.