The establishment of neuronal connections, called synapses, is a major milestone in human brain development that is necessary for cognitive processes such as learning, memory and motor function. Synapses are specialized connections that allow nerve cells (neurons) to communicate. Abnormalities in their structure and function underlie neurodevelopmental disorders (eg. Autism Spectrum Disorder [ASD]) and psychiatric disease (eg. Bipolar Disorder and Schizophrenia). These disorders negatively impact the daily lives of affected individuals, causing an economical and social burden, but due to a poor understanding of their biological mechanisms, there are no cures. This underscores the need to better understand how abnormal brain development causes disease. There is strong emerging evidence that molecules belonging to a class called Wingless (Wnt) signaling in the brain play a significant role in disease. Furthermore, there are multiple lines of evidence (human genetic studies, animal models and medications used in the clinic) that indicate disrupting Wnt signaling causes profound synaptic defects and ASD-like pathologies. This suggests studying Wnt signaling molecules may reveal new mechanisms underlying disease pathophysiology. In this study, we examine a new candidate molecule named Dix domain containing 1 (DIXDC1) to determine its role in neuronal growth, synaptic development and ASD pathophysiology. This project will examine DIXDC's role as a new molecular player in synaptic function, and explore a novel signaling pathway regulating DIXDC1 function. Importantly, we have discovered new ASD-linked mutations in DIXDC1 using next-generation sequencing, and we will examine how these human mutations cause brain dysfunction. Together, our experiments will provide new information that will help us understand how Wnt signaling molecules are involved in normal synaptic development, and how their disease-associated abnormalities leads to ASD pathological consequences.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
