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A new study by researchers at the Hospital del Mar Research Institute and Yale University suggests that the origins of several brain-related disorders may be found in the earliest stages of fetal brain development. The findings, published in Nature Communications, show that many genes associated with neuropsychiatric and neurodegenerative diseases are active in neural stem cells, well before birth.
The research focused on nearly 3,000 genes linked to conditions such as autism, bipolar disorder, depression, schizophrenia and neurodegenerative diseases including Alzheimer’s and Parkinson’s. Using a combination of human and mouse data, alongside in vitro cellular models, the team simulated how genetic disruptions might affect the development of the fetal brain.
Simulating genetic disruptions in neural stem cells
Neural stem cells give rise to all the cell types of the brain, including neurons and their support cells. The study explored how gene alterations influence these progenitor cells during different stages of development. Researchers modelled regulatory networks for each relevant cell type and assessed how activating or silencing disease-linked genes affected their behaviour.
Neural stem cells
These are self-renewing cells in the developing brain that generate neurons and glial cells. They play a crucial role in forming brain structures during fetal development.
Regulatory networks
In biology, these are systems of interacting genes, proteins, and other molecules that control gene expression and cellular behaviour. They are key to understanding how genes function in specific contexts.
This approach allowed the team to identify when and where specific genes are most active, providing a clearer picture of how early genetic alterations may lead to brain structure and function changes later in life. Disorders ranging from cortical malformations, such as microcephaly and hydrocephaly, to anorexia, depression and schizophrenia were included in the analysis.
“Scientists usually study the genes of mental illnesses in adults, but in this work we discovered that many of these genes already act during the early stages of fetal brain formation, and that their alterations can affect brain development and promote mental disorders later on”.
Dr. Nicola Micali.
Cortical malformations
These refer to structural abnormalities in the cerebral cortex, the brain’s outer layer, which can lead to neurological and developmental disorders.
Broader implications for understanding disease mechanisms
The study suggests that disruptions to gene function in neural stem cells could contribute to a wide range of conditions affecting the cerebral cortex. It also highlights specific developmental windows when these genes are especially influential, which could be critical for identifying periods of heightened vulnerability or therapeutic opportunity.
The findings may contribute to future efforts in understanding how early brain development impacts mental and neurological health. They also lay the groundwork for more targeted studies into gene function during neurodevelopment, potentially informing future gene-based treatment approaches.
Reference: Mato-Blanco X, Kim SK, Jourdon A, et al. Early developmental origins of cortical disorders modeled in human neural stem cells. Nat Commun. 2025;16(1). doi: 10.1038/s41467-025-61316-w
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