Project Summary/Abstract Individuals with a supernumerary X chromosome such as those with Klinefelter syndrome (XXY) or Triple X syndrome (XXX) often have congenital abnormalities that include reduced neurological function. The presence of extra copies of the X chromosome results in extra copies of genes that escape X inactivation. Thus, abnormally high dosage of escape genes is an attractive target for the causation of phenotypes seen in common supernumerary X syndromes. KDM5C, one of the genes that escapes X inactivation, represents a particularly attractive candidate because it is a dosage-sensitive master regulator important for promoter and enhancer regulation and neurological function. Indeed, patients with deletion or duplication of the gene have intellectual disability. To address the role of Kdm5c over expression we will employ a unique mouse model with skewed X inactivation and precise over expression of Kdm5c due to insertion of one extra copy of the gene. Other animal models of Klinefelter or Triple X syndromes have been reported, however it is impossible to determine the effects of increased dosage of a particular escape gene in such models since the entire cohort of escape genes is overexpressed. It is probable that neurological phenotypes observed in supernumerary X syndromes stem from developmental defects during embryogenesis. Thus, to determine the effects of Kdm5c over expression on the pathways critical for neurogenesis we use a novel mouse model which specifically over expresses Kdm5c and monitor in vivo genetic and epigenetic changes genome-wide during neural development at critical time points associated with neurogenesis in the embryo. Gene expression changes and epigenetic changes will be integrated to identify and map genes and controlling elements affected by over expression of Kdm5c. Our goals are to determine whether gene expression and epigenetic modifications are dysregulated during neurodevelopment in embryos where Kdm5c is over expressed. Our comprehensive in vivo approaches will provide new insights in understanding the role of escape gene dosage in relevant neurological phenotypes manifested in common X chromosome aneuploidy syndromes.