Induced Pluripotent Stem Cells & Developmental Disorders

Over the last several years we derived more than 500 iPSC lines from patients with developmental disorders as a window into normal and abnormal neuronal development. We established new protocols for converting iPSCs into brain organoids that reflect the human cerebral cortex or basal ganglia at early-fetal stages of development, including the main 5 classes of excitatory cortical neurons, medium spiny neurons, cholinergic neurons, and inhibitory interneurons. Using this model, our group has recently discovered neurodevelopmental alterations in autism spectrum disorders, revealing an important role of the transcription factor FOXG1 in the overproduction of inhibitory neuron progenitors in idiopathic autism with macrocephaly (Mariani et al, 2015). Ongoing studies in organoids are investigating neurodevelopment in Tourette syndrome. As part of the PsychENCODE collaborative multi-site project, we generated a genome-scale catalog of enhancers and their associated gene products active in early brain development (in revision). These data place organoids at embryonic and early-fetal stages of human brain development, and establish links between genes/enhancers active at these early stages and risk alleles for human developmental disorders and regulatory elements driving human brain evolution.