"Modeling Prenatal Cortical Development Using Induced Pluripotent Stem Cells"
Flora M. Vaccarino, MD
Harris Professor at the Child Study Center;
Professor in the Dept. of Neuroscience, Yale University of Medicine
We have a poor understanding of the pathogenesis of neurodevelopmental disorders, owing to the fact that post-mortem and imaging studies offer little insight into the processes that give rise to the observed outcomes. Human induced pluripotent stem cells (hiPSCs) in principle should prove powerful in elucidating the pathways that give rise to neurodevelopmental disorders. By allowing the direct study of gene expression and function as neural cells divide and differentiate, hiPSC model systems promise to bridge the gap between genomic variation and its effects on neuronal circuitry and function. To illuminate the pathophysiology of neurodevelopmental disorders of complex etiology, we used iPSC lines to generate neural organoids mimicking the fetal development of the neocortex. We find that organoids exhibit region- and stage-dependent transcriptomes, approaching a stage corresponding to15-16 post-conceptional weeks of human cortical development. Mapping enhancer element activity using histone marks suggests similarity between organoids and fetal human neocortex and dissimilarity with adult neocortex. We used this model to investigate the pathogenesis of idiopathic autism spectrum disorder (ASD). Using transcriptome and gene network analyses, we found that an overexpression of the transcription factor FOXG1 is responsible for an overproduction of GABAergic neurons from ASD progenitors. We conclude that iPSCs can be useful to elucidate the pathophysiology of complex human disorders and represent a promising model for diagnostics, drug discovery, therapeutics and personalized medicine.
TUESDAY: March 28, 2017 at 4:30 pm
The Northwest Bldg, Room B101
52 Oxford Street
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