WNT/B-catenin dependant alteration of cortical neurogenesis in a human stem cell model of SETBP1 disorder

Disruptions of SETBP1 (SET binding protein 1) on 18q12.3 by heterozygous gene deletion or loss-of-function variants cause SETBP1 disorder. Clinical features are frequently associated with moderate to severe intellectual disability, autistic traits and speech and motor delays. Despite SETBP1 association with neurodevelopmental disorders, little is known about its role in brain development. Using CRISPR/CAS9 genome editing technology, we generated a SETBP1 deletion model in human embryonic stem cells (hESCs), and examined the effects of SETBP1-deficiency in in vitro derived neural progenitors (NPCs) and neurons using a battery of cellular assays, genome wide transcriptomic profiling and drug-based phenotypic rescue. SETBP1-deficient NPCs exhibit protracted proliferation and distorted layer-specific neuronal differentiation with overall decrease in neurogenesis. Genome wide transcriptome profiling and protein biochemical analysis showed that SETBP1 deletion led to enhanced activation of WNT/{beta}-catenin signaling. Crucially, treatment of the SETBP1-deficient NPCs with a small molecule WNT inhibitor XAV939 restored hyper canonical {beta}-catenin activity and rescued cortical neuronal differentiation. Our study establishes a novel regulatory link between SETBP1 and WNT/{beta}-catenin signaling during human cortical neurogenesis and provides mechanistic insights into structural abnormalities and potential therapeutic avenues for SETBP1 disorder.