O-GlcNAc transferase Ogt regulates embryonic neuronal development through modulating Wnt/β-catenin signaling.

Ogt-mediated O-GlcNAcylation is enriched in the nervous system, and involves in neuronal development, brain function and neurological diseases. However, the roles of Ogt and O-GlcNAcylation in embryonic neurogenesis has remained largely unknown. Here, we show that Ogt is highly expressed in embryonic brain, and Ogt depletion reduces the proliferation of embryonic neural stem cells and migration of new born neurons. Furthermore, Ogt in cultured hippocampal neurons impaires neuronal maturation including reduced dendritic numbers and length, and immature development of spines. Mechanistically, Ogt depletion decreases the activity of Wnt/β-catenin signaling. Ectopic β-catenin rescues neuronal developmental deficits caused by Ogt depletion. Ogt also regulates human cortical neurogenesis in forebrain organoids derived from induced pluripotent stem cells. Our findings reveal the essential roles and mechanisms of Ogt-mediated O-GlcNAc modification in regulating mammalian neuronal development.