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Abstract

Neurodevelopmental disorders, including autism spectrum disorders (ASD) and intellectual disability (ID), affect nearly 1 in 44 children in the United States and are caused by mutations in any one of over 1000 genes. A subset of these genes is “dosage-sensitive” where both under- and over-expression causes a neurological disorder. Understanding how small changes in these dosage-sensitive genes drive disease pathogenesis has been challenging in part because we cannot uncouple primary molecular changes from those secondary to declining neuronal health. In this seminar, I will demonstrate how studying the dynamic transcriptional and epigenomic response to an acute change in gene dosage in the adult brain revealed insight into the pathogenesis of two disorders – Rett syndrome (RTT) and MECP2 duplication syndrome (MDS), each caused by altered dosage of the X-linked gene methyl-CpG binding protein 2 (MECP2). Through analyses of time series phenotypic, physiological, and -omics data, I identified the most proximal changes driving disease and discovered Growth differentiation factor 11 (GDF11) expression is disrupted early in both RTT and MDS. Intriguingly, I found that restoring Gdf11 expression ameliorated several behavioral deficits in a mouse model of MDS. This led to the discovery that Gdf11 dosage itself is critical for normal neuronal function in both mouse and humans and is a potential therapeutic target for multiple neurodevelopmental disorders.