Work

Modeling Mowat-Wilson syndrome with patient iPSCs reveals transcriptional and phenotypic defects in neural progenitors

Year: 2025

Type: article

Abstract: Zinc finger E -box-binding homeobox 2 ( ZEB2 ) is a key transcription factor involved in multiple aspects of nervous system development, including neuronal specification, migration, and differentiation. Loss-of-function variants in ZEB2 cause Mowat-Wilson syndrome (MWS), a severe neurodevelopmental disorder characterized by intellectual disability, epilepsy, and brain structural abnormalities. In this study, we generated and characterized induced pluripotent stem cell (iPSC) lines from MWS patients carrying pathogenic ZEB2 variants. Patient-derived iPSCs retained full pluripotency and were capable of differentiating into all three germ layers, including neural lineages. Upon directed differentiation into neural progenitor cells (NPCs) and early neurons, we identified distinctive transcriptional alterations affecting neuroepithelial-to-radial glia transition and lineage specification. RNA-seq analysis revealed dysregulation of genes involved in cytoskeletal remodeling, extracellular matrix organization, and cell motility. Functional holographic live imaging confirmed a significant increase in motility behavior in MWS NPCs and early neurons, suggesting that altered cell dynamics may underlie aberrant neural circuit formation. Despite these changes, early neuronal markers such as MAP2 were expressed at comparable levels in MWS and control cells. Together, these findings uncover novel cellular and molecular phenotypes associated with ZEB2 deficiency and provide insight into how disrupted progenitor behavior and transcriptional mis-regulation may contribute to the neurodevelopmental features of MWS. • ZEB2 variants cause Mowat-Wilson syndrome (MWS) with severe neural abnormalities. • MWS iPSCs retain pluripotency but show altered neural differentiation. • MWS neural progenitors fail to repress non-neural genes, activating ECM and vascular pathways. • Patient-derived iPSCs provide a human model for studying MWS pathogenesis.

Source: Neurobiology of Disease

DOI: 10.1016/j.nbd.2025.107205