POU3F2 acts as a master regulator of neurodevelopment and neural homeostasis through its modulation of Wnt-mediated progenitor expansion and neuronal maturation

POU3F2 is a neural-specific POU class III transcription factor that has been widely implicated in the etiology of neurodevelopmental disorders. Loss-of-function mutations in POU3F2 have been identified in individuals presenting with intellectual disability, neurodevelopmental delay, and autism spectrum disorder (ASD) (Kasher et al., 2016; Schonauer et al., 2023). In genome-wide association studies, POU3F2 has been one of the few loci repeatedly associated with increased risk for bipolar disorder (Mullins et al., 2021). While these studies clearly underscore the importance of proper POU3F2 activity in humans, little is known about the mechanisms underlying its connection to neurological disorders. To elucidate the mechanistic role of POU3F2 in human neurodevelopment, we induced POU3F2 disruption in human induced pluripotent stem cells (iPSCs), which we then differentiated into neural progenitor cells (NPCs). Mutation of POU3F2 in NPCs causes reduced baseline canonical Wnt signaling, decreased proliferation, and premature specification of radial glia. In addition, POU3F2 levels across genetically diverse NPCs significantly associate with baseline canonical Wnt signaling and expression of radial glia markers. Through a series of unbiased analyses, we show that SOX13 and ADNP are transcriptional targets of POU3F2 that mediate POU3F2’s effects on Wnt signaling to allow for regulated expansion of the progenitor pool. We further investigated the role of POU3F2 in neuronal maturation by differentiating POU3F2-disrupted iPSCs into cortical excitatory induced neurons (iNs). POU3F2-disrupted iNs exhibit decreased neurite outgrowth and reduced neuronal activity, as measured by multi-electrode array. Conversely, these neurons show upregulation of genes involved in synaptic development and a concurrent increase in synapse numbers. These findings suggest that POU3F2 represses genes involved in synaptogenesis to allow for early maturation and arborization of post-mitotic neurons. Finally, we describe an additional five individuals with ASD that exhibit loss-of-function mutations in POU3F2. Together, these studies clearly implicate POU3F2 as a master regulator of neurodevelopment and neuronal maturation and provide evidence for the prioritization of POU3F2 as a high-confidence risk gene underlying the etiology of neurodevelopmental disorders.