more homogeneous in structure, composed of repeating units of rosettes, and for which RNA sequencing comparison to the BrainSpan dataset revealed closest similarity to early fetal brain tissue. She cautioned that specific transcriptome differences exist between isogenic intact organoids and dissociated progenitors. Noting that an increase in brain and head size (i.e., macrocephaly) characterizes a subset of ASD patients with poorer outcome, Vaccarino described a study where organoids from patients were systematically compared to those from their fathers in transcriptomics and cellular phenotypes. She reported that ASD hiPSC-derived organoids show a complex cellular phenotype that includes decreased cell cycle length, upregulation of genes directing gamma-amino butyric acid (GABA) neuron fate, increased synaptogenesis and dendrite outgrowth, and changes in synaptic activity. Global gene co-expression network analysis of cortical organoids resolved a number of gene modules that were differentially expressed in ASD individuals, including one potentially driven by FOXG1, a master regulatory transcription factor that was greatly upregulated in ASD. Interestingly, knockdown of FOXG1 in ASD-derived iPSCs normalized the shift in GABA phenotype in ASD cortical organoids, suggesting a potential causal pathway in the ASD GABAergic imbalance phenotype (Mariani et al., 2015).
