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

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 distinct transcriptional alterations affecting neuroepithelial-to-radial glia transition, glial lineage specification, and neuronal subtype identity. 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 misregulation may contribute to the neurodevelopmental features of MWS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE311389 | GEO | 2025/12/05

REPOSITORIES: GEO

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Project description:Cell-based models of many neurological and psychiatric diseases, established by reprogramming patient somatic cells into human induced pluripotent stem cells (hiPSCs), have now been reported. While numerous reports have demonstrated that neuronal cells differentiated from hiPSCs are electrophysiologically active mature neurons, the âageâ of these cells relative to cells in the human brain remains unresolved. Comparisons of gene expression profiles of hiPSC-derived neural progenitor cells (NPCs) and neurons to the Allen BrainSpan Atlas indicate that hiPSC neural cells most resemble first trimester neural tissue. Consequently, we posit that hiPSC-derived neural cells may most accurately be used to model the early developmental defects that contribute to disease predisposition rather than the late features of the disease. Though the characteristic symptoms of schizophrenia SZ generally appear late in adolescence, it is now thought to be a neurodevelopmental condition, often predated by a prodromal period that can appear in early childhood. Postmortem studies of SZ brain tissue typically describe defects in mature neurons, such as reduced neuronal size and spine density in the prefrontal cortex and hippocampus, but abnormalities of neuronal organization, particularly in the cortex, have also been reported. We postulated that defects in cortical organization in SZ might result from abnormal migration of neural cells. To test this hypothesis, we directly reprogrammed fibroblasts from SZ patients into hiPSCs and subsequently differentiated these disorder-specific hiPSCs into NPCs. SZ hiPSC differentiated into forebrain NPCs have altered expression of a number of cellular adhesion genes and WNT signaling. Methods: We compared global transcription of forebrain NPCs from six control and four SZ patients by RNAseq. Results: Multi-dimensional scaling (MDS) resolved most SZ and control hiPSC NPC samples; 848 genes were significantly differentially expressed (FDR<0.01) Conclusions: The WNT signaling pathway was enriched 2-fold (fisher exact test p-value = 0.031). 1-2 independent differentiations (biological replicates) for each of four control and four schizophrenia patients were analyzed; samples were generated in parallel to neuron RNAseq data.

Project description:Cell-based models of many neurological and psychiatric diseases, established by reprogramming patient somatic cells into human induced pluripotent stem cells (hiPSCs), have now been reported. While numerous reports have demonstrated that neuronal cells differentiated from hiPSCs are electrophysiologically active mature neurons, the “age” of these cells relative to cells in the human brain remains unresolved. Comparisons of gene expression profiles of hiPSC-derived neural progenitor cells (NPCs) and neurons to the Allen BrainSpan Atlas indicate that hiPSC neural cells most resemble first trimester neural tissue. Consequently, we posit that hiPSC-derived neural cells may most accurately be used to model the early developmental defects that contribute to disease predisposition rather than the late features of the disease. Though the characteristic symptoms of schizophrenia SZ generally appear late in adolescence, it is now thought to be a neurodevelopmental condition, often predated by a prodromal period that can appear in early childhood. Postmortem studies of SZ brain tissue typically describe defects in mature neurons, such as reduced neuronal size and spine density in the prefrontal cortex and hippocampus, but abnormalities of neuronal organization, particularly in the cortex, have also been reported. We postulated that defects in cortical organization in SZ might result from abnormal migration of neural cells. To test this hypothesis, we directly reprogrammed fibroblasts from SZ patients into hiPSCs and subsequently differentiated these disorder-specific hiPSCs into NPCs. SZ hiPSC differentiated into forebrain NPCs have altered expression of a number of cellular adhesion genes and WNT signaling. Methods: We compared global transcription of forebrain NPCs from six control and four SZ patients by RNAseq. Results: Multi-dimensional scaling (MDS) resolved most SZ and control hiPSC NPC samples; 848 genes were significantly differentially expressed (FDR<0.01) Conclusions: The WNT signaling pathway was enriched 2-fold (fisher exact test p-value = 0.031).

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

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