In the present study, we observed similar anatomical changes in the organoids of all three patients that have distinct genetic backgrounds and DNA sequences, which could be linked to schizophrenia. However, the iPSC-derived NPCs all showed a common disruption of 1376 genes in the developmental transcriptome29. Thus, our studies reinforce the watershed model of schizophrenia, whereby different mutations lead to the common dysregulation of the neuro-ontogenic genome and to the common cortical maldevelopment. Our findings designate INFS as a common important mechanism in the disease. According to the model shown in Fig. 8d, nFGFR1 hyperactivity leads initially to the excessive migration of proliferating NPCs and then their premature differentiation within subcortical regions. Later, during corticogenesis, turning off nFGFR1 in the schizophrenia cortical cells disrupts their further development. Future investigation, including restoration of INFS in the developing schizophrenia cortex, will test this hypothesis and potentially be used in preventive therapies.
