a Distribution of FGFR1 in zones of hESC H9 organoids (fluorescent microscope images). b Reduction of nFGFR1 in CZ after PD173074 treatment (days 8–18)—confocal analysis of FGFR1 and DAPI co-staining; (b1) control and (b2) PD173074-treated cerebral organoids. (b3) control and (b4) PD173074, areas zoomed 63×. c Percentage of nFGFR1 expressing cells in CZ was reduced by PD173074—nFGFR1+ nuclei were counted in sets of 100 DAPI-stained nuclei. d Left—reference stratification of developing telencephalon and zones of cerebral organoids—ventricular (VZ), intermediate (IZ), cortical (CZ), marginal (MZ); middle and right—summary of results—in schizophrenia organoids, we found the following changes: (i) increased proliferation of Ki67 NPCs and migration outside the VZ into the IZ and CZ, (ii) diminished deposition of reelin in the developing cortex (known to guide cortico-petal migration), (iii) reduced cortical accumulation of pioneer TBR1 neurons and reduced formation of cortical neurons, (iv) stunted cortical neuronal development accompanied by a robust formation of the subcortical neurons, and (v) fewer calretinin interneurons forming horizontal processes (known to connect cortical columns). The premature development of NPCs into subcortical neurons may reflect excessive nFGFR1 (+)* signaling in differentiating schizophrenia NPCs (as found in earlier genomic studies55). On the other hand, stunted cortical development likely reflects the loss of cortical nFGFR1 signaling. Modeling this loss in hESC organoids, by blocking FGFR1 signaling and depleting nFGFR1 with PD173074, replicates the impaired cortical development observed in schizophrenia iPSC organoids. The loss of cortical nnFGFR1 may underlie the stunted cortical development in schizophrenia
