Analysis of brain development, disease, and evolution via organoids

The general patterning of the human brain occurs during very early maturation stages, for which the availability of primary human tissue is very scarce. Thus, despite their limits, here organoids derived from human induced Pluripotent Stem Cells (hiPSCs) are proposed as a reliable and reproducible model to obtain single cell expression data (via single cell RNA sequencing) useful to investigate brain development, disease and evolution. Analyzing the resulting data, it emerged that the transition from stem cells to progenitors is the most vulnerable phase in early brain development. As regards brain disease, results point the relevance of enhancers and their non-coding variants in Autism Spectrum Disorder (ASD). Furthermore, the results highlight the relevance of Human-Gained Enhancers (HGEs) in the regulation of the evolutionary process of cortical radial glia expansion. At last, the comparison among expression data derived from human primary and organoid tissues, macaque primary tissues, and chimp brain organoids, suggests that gene duplication could be a key event for human-specific brain evolution as well as the increased regulation of the PI3K-AKT-mTOR signaling pathway.