Multiomics analysis identifies VPA-induced changes in neural progenitor cells, ventricular-like regions, and cellular microenvironment in dorsal forebrain organoids.

Overview

1. The Heidelberg Academy of Sciences and Humanities,Heidelberg, Germany
2. Hertie Institute for Clinical Brain Research, University of Tübingen,Tübingen, Germany
3. International Max Planck Research School, Graduate Training Centre of Neuroscience, University of Tübingen,Tübingen, Germany
4. Graduate Training Centre of Neuroscience, University of Tübingen,Tübingen, Germany
5. Systemic Cellular Neurobiology, Zoological Institute, Karlsruhe Institute of Technology (KIT),Karlsruhe, Germany
6. University of Tübingen,Tübingen, Germany
7. Core Facility for Medical Proteomics, Institute for Ophthalmic Research, University Clinic Tübingen,Tübingen, Germany
8. Institute for Molecular Systems Engineering and Advanced Materials (IMSEAM), Heidelberg University,Heidelberg, Germany
9. Institute of Biological and Chemical Systems - Functional Molecular Systems, Karlsruhe Institute of Technology (KIT),Eggenstein-Leopoldshafen, Germany

Abstract

Pharmaceutical agents, such as antiepileptic medications, can cross fetal barriers and affect the developing brain. Prenatal exposure to the antiepileptic drug valproate (VPA) is associated with an increased risk of neurodevelopmental disorders, including congenital malformations and autism spectrum disorder. In animal models and neural organoids, VPA has been shown to alter signaling pathways, such as Wnt pathway, providing insights into VPA-induced neurodevelopmental defects. Here, we exposed dorsal forebrain organoids to VPA for 30 days and examined effects at the tissue, cellular, and molecular level. VPA treatment disrupted ventricular-like regions, indicating defects in cell-cell and cell-matrix interactions. Transcriptomics analysis confirmed altered expression of extracellular matrix (ECM) genes and single cell RNA sequencing analysis identified genes involved in microenvironment sensing, such as cellular mechanosensing and Hippo-YAP/TAZ signaling pathway. Finally, proteomics analysis corroborated that VPA alters the microenvironment of the human dorsal forebrain organoids by disrupting the secretion of ECM proteins. Altogether, our study suggests that VPA-treated dorsal forebrain organoids serve as a model to investigate the role of extracellular processes in brain development and to understand how their disruptions might contribute to neurodevelopmental disorders.

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All bulk RNA sequencing data is submitted to ArrayExpress and is available under the ID E-MTAB-15191. Single cell RNA sequencing data is submitted to CellxGene and is available under the URL: https://cellxgene.cziscience.com/collections/c2879de0-affc-496b-8e2b-f57ed9ec3c34. All MS data and MS data analysis dataset are submitted to MassIVE and can be accessed under the ID MSV000097991 or ProteomeXchange repository under the accession ID PXD064286. The MS data with only Ctrl DFOs has been used in another manuscript and is available in MassIVE under the accession ID MSV000094878 or ProteomeXchange repository under the accession ID PXD052612. Supplementary information is available at MP’s website.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Recorded: type, language, journal, volume, issue, pages, dates, 13 authors, 3 keywords, 16 MeSH terms, 10 funders, 85 references.

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Yentür, Z., Branco, L., Sarieva, K., Andreeva, D., Kagermeier, T., Kulka, C., Jarboui, M. A., Colombo, F., Diaz, F., Collignon, P., Becker, K., Selhuber-Unkel, C., & Mayer, S. (2026). Multiomics analysis identifies VPA-induced changes in neural progenitor cells, ventricular-like regions, and cellular microenvironment in dorsal forebrain organoids. Molecular psychiatry, 31(9), 4977-4994. https://doi.org/10.1038/s41380-026-03585-5

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