ability of lithium to activate WNT signaling12–14, we hypothesized that activation of WNT signaling through GSK3 inhibition would be sufficient to rescue the NPC proliferation deficits observed in the FACS-purified, BD patient-derived CXCR4+. In agreement with this notion, as shown in Figure 5F and Supplemental Figure 16, treatment with CHIR-99021 (5 µM; 16 hr), a highly selective and potent GSK3 inhibitor41,58, led to a significant increase in BrdU incorporation in both BD-patient NPC lines. In parallel, we assessed the response of the NPCs to CHIR-99021 treatment at the level of expression of known WNT pathway genes using our PsychGene NanoString probe set. As summarized in (Fig. 5G), CHIR-99021 treatment (5 µM; 16 hr) increased the expression of the β-catenin target genes LEF1 (Lymphoid enhancer-binding factor 1) and AXIN2 (Axis inhibition protein 2), both of which are critical regulators of canonical WNT signaling. Taken together, these results suggest that WNT pathway activation can rescue the neurogenesis defects observed in the BD-patient CXCR4+ NPCs from the Family-811 quartet.
