Loss of POGZ alters neural differentiation of human embryonic stem cells

POGZ is a pogo transposable element derived protein with multiple zinc finger domains. Many de novo loss-of-function (LoF) variants of the POGZ gene are associated with autism and other neurodevelopmental disorders. However, the role of POGZ in human cortical development remains poorly understood. Here we generated multiple POGZ LoF lines in H9 human embryonic stem cells (hESCs) using CRISPR/Cas9 genome editing. These lines were differentiated into neural structures analogous to those in early to mid-fetal human brain, a critical developmental stage for studying neurodevelopmental disease mechanisms. We found that loss of POGZ reduced neural stem cell proliferation in excitatory cortex-patterned neural rosettes (structures analogous to the cortical ventricular zone in fetal brain). As a result, fewer intermediate progenitor cells and early-born neurons were generated. In addition, neuronal migration from the apical center to the basal surface of neural rosettes was perturbed by loss of POGZ. Furthermore, cortical-like excitatory neurons derived from multiple POGZ homozygous knockout lines exhibited a more simplified dendritic architecture compared to wild-type. Our findings demonstrate how POGZ regulates early neurodevelopment in human cells, providing insight into the cellular pathogenesis of POGZ-related neurodevelopmental disorders.