Modeling Histone Demethylase Function in Neurogenesis

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ABSTRACT Cortical development is dependent on the coordinated expression of critical genes for proper cognitive function. Alterations in expression of these key genes during development can result in complex neurological diseases. Epigenetic mechanisms dynamically regulate expression of key genes and their loss of function disrupts cortical development and contributes to brain disorders. Rare pathogenic mutations in one epigenetic factor, KDM3B, are linked to intellectual disability and autism spectrum disorders (ASD). This exploratory proposal will test the functional consequences of these KDM3B mutations on cortical development using human embryonic stem cells with mutations of KDM3B. We will investigate both cellular and molecular differences between mutant and control cells as they differentiate into neural progenitor cells and neurons. Integration of these cellular data with molecular data will reveal the direct effects of intellectual disability related mutations in KDM3B to neurodevelopment.