POU3F2 regulates canonical Wnt signalling via SOX13 and ADNP to expand the neural progenitor population

Abstract

Loss-of-function mutations in the transcription factor POU3F2 have been identified in individuals with neurodevelopmental disorders. To elucidate the mechanistic role of POU3F2 in human neurodevelopment, we induced POU3F2 disruption in human neural progenitor cells (NPCs). Mutation of POU3F2 in NPCs causes reduced baseline canonical Wnt signalling and decreased proliferation, resulting in premature specification of radial glia. Additionally, POU3F2 levels across genetically diverse NPCs significantly associate positively with baseline canonical Wnt signalling and negatively with markers of radial glia specification. Through a series of unbiased analyses, we show that SRY-box transcription factor 13 (SOX13) and activity dependent neuroprotector homeobox (ADNP) are transcriptional targets of POU3F2 which mediate POU3F2's effects on Wnt signalling in human NPCs. Finally, we describe five individuals with autism spectrum disorder that harbour loss-of-function mutations in POU3F2, enhancing the genetic evidence for its critical role in human neurodevelopment. Together, these studies define POU3F2 as an activator of canonical Wnt signalling and mechanistically link two high-confidence autism genes, ADNP and POU3F2, in the regulation of neurodevelopment.

Keywords: CRISPR/Cas9; autism spectrum disorder (ASD); canonical Wnt signalling; induced pluripotent stem cells (iPSCs); neural progenitor cells (NPCs); neurodevelopmental disorders.