The impaired cortical development of schizophrenia organoids correlated with a striking loss of nFGFR1 from the CZ cells observed already at 2 weeks and was verified by a statistically significant loss in 5-week organoids of all investigated patients. The loss of nFGFR1 was limited to cortical cells, as FGFR1 remained highly expressed in the VZ and IZ of schizophrenia organoids throughout the 5 weeks of development. Given the well-established role of nFGFR1 in cell differentiation and neuronal development18,20 (-reviews), the loss of nFGFR1 from the nuclei of differentiating cortical neuronal cells in schizophrenia organoids likely underlies the impaired neuronal differentiation and cortical maldevelopment observed in schizophrenia. Furthermore, blocking of nFGFR1 in NPCs and NCCs impacted a number of the key ontogenic and neuro-ontogenic gene categories involved in neuronal development, forebrain development, cell adhesion and migration, axon formation, and guidance and in the established neuro-ontogenic pathways. Our genomic analyses also revealed that the loss of nFGFR1 function in NPCs affected several of the reelin signaling genes (Supplementary Fig. 6c), which together with the loss of reelin, denotes the malfunctioning reelin mechanism in the schizophrenia cortex.
