Altered WNT Signaling in Human Induced Pluripotent Stem Cell Neural Progenitor Cells Derived from Four Schizophrenia Patients.

Schizophrenia (SZ) is a devastating psychiatric disorder hypothesized to be a neurodevelopmental condition (1,2) arising as a consequence of dysregulation of brain development (3,4). WNT signaling is important for neural patterning, proliferation and migration, and synapse formation (5); converging postmortem (6,7), rodent (8,9), and pharmacologic (10) evidence suggests that WNT signaling may contribute to SZ (11,12). We used human induced pluripotent stem cell (hiPSC) derived forebrain patterned neural progenitor cells (NPCs) (13,14) to investigate canonical WNT activity in a pilot cohort of four patients with SZ. Because all research described herein was performed on deidentified human samples obtained for broadly consented scientific research by either American type culture collection or the Coriell Cell Repository, it was found to be exempt by the Internal Review Committee of the Icahn School of Medicine at Mount Sinai. This work was also reviewed by the Embryonic Stem Cell Research Oversight Committee at the Icahn School of Medicine at Mount Sinai. We compared global transcription of forebrain hiPSC NPCs from six control subjects and four patients with SZ by RNA sequencing (GSE63738) (Table 1), cultured as described (13,14). As previously reported, hiPSC forebrain NPCs differentiate to a mixed neuronal population of glutamatergic and GABAergic neurons; there was no difference in the ability of control or SZ hiPSC NPCs to generate βIII-tubulin–positive neurons (14), and neither transcriptional nor immunohistochemical characterization revealed any diagnosis-dependent differences in the regional patterning of forebrain NPCs (13). Multidimensional scaling resolved most SZ and control hiPSC NPC samples (Figure 1A); 848 genes were significantly differentially expressed (false discovery rate , .05) (Table S1 in Supplement 1), as illustrated by a heat map (Figure 1C) and a volcano plot (Figure 1D). The differentially expressed genes in SZ hiPSC NPCs were significantly 3.6-fold enriched compared with WNT target genes (p , 10e-20) predicted by standard classification and regression tree methods (16). The