Induced Pluripotent Stem Cells & Developmental Disorders

Over the last several years we derived hundreds of iPSC lines from patients with developmental disorders as a window into normal and abnormal neuronal development. We established a new protocol for converting iPSCs into brain organoids that reflect the human cerebral cortex at mid-fetal stages of development, including the main 5 classes of excitatory cortical neurons and inhibitory interneurons. Using this tool, our group has recently contributed fundamental work on neurodevelopmental alterations in autism spectrum disorders, revealing an important role of the transcription factor FOXG1 in idiopathic autism. Transcriptome and cell fate studies in organoids from children with idiopathic autism and unaffected family members indicated alterations in cell proliferation, overproduction of synapses and a striking increase in GABAergic neurons and their precursors, caused in part by an aberrant increase in FOXG1 gene expression (Mariani, Coppola et al, Cell, 2015). Ongoing studies integrate genomes, transcriptomes and cellular phenotypes to explore the etiology of autism and other neurodevelopmental alterations. As part of the PsychENCODE collaborative multi-site project, the lab will generate a genome-scale catalog of coding and noncoding RNAs and functional DNA elements in iPSC-derived organoids and human brain specimens. Our object within the PsychENCODE is to verify to what extent the iPSC-derived organoids reflect true human brain development.