Key Questions Answered:
Q: When do genes linked to mental illness start affecting the brain?
A: A substantial number of genes associated with neuropsychiatric and neurodegenerative conditions become active during the earliest stages of fetal brain development—much earlier than many researchers previously assumed.
Q: How did researchers uncover this early genetic activity?
A: The team simulated the effects of almost 3,000 disease-associated genes on fetal neural stem cells by integrating human and mouse datasets with in vitro cell models, allowing them to map when and where these genes influence brain-building processes.
Q: Why is this discovery important for treatment?
A: Pinpointing which genes act in specific cell types and developmental windows creates opportunities for earlier diagnosis and for developing targeted, personalized therapies that intervene at the biological root of neurodevelopmental and neurodegenerative disorders.
Summary: A new study shows that many genes tied to conditions such as autism, schizophrenia, depression, Alzheimer’s, and Parkinson’s are already functional in neural stem cells during very early fetal brain formation. These genes are active long before symptoms appear, which reframes when and how disease processes can begin and highlights windows of vulnerability and therapeutic opportunity.
Combining human and mouse brain data with laboratory-grown human neural stem cell models, researchers reconstructed gene expression and regulatory network dynamics across developmental stages and cell types. This integrative approach identifies critical periods and cell populations in which genetic risk factors are most likely to disrupt normal cortical development.
Key Facts:
- Early Origins: Many disease-associated genes are active in fetal neural stem cells, the progenitors that generate neurons and glial support cells.
- Broad Disease Spectrum: Risk genes linked to disorders ranging from microcephaly and hydrocephaly to autism, bipolar disorder, anorexia, schizophrenia, Alzheimer’s, and Parkinson’s show activity in early development.
- Therapeutic Potential: Identifying when and where these genes act can guide early interventions, gene-targeted therapies, and personalized treatment strategies.
Source: IMIM
Early developmental origins of some neuropsychiatric and neurodegenerative diseases
Research led by the Hospital del Mar Research Institute in collaboration with Yale University, and published in Nature Communications, indicates that the roots of many cortical disorders trace back to the earliest phases of fetal telencephalic development. The study focused on neural stem cells (NSCs), the early progenitor cells responsible for building the cerebral cortex.
Dr. Gabriel Santpere, Miguel Servet researcher and coordinator of the Neurogenomics Research Group at the Biomedical Informatics Research Program of the Hospital del Mar Research Institute, explains that the study set out to trace the origins of mental illnesses to the earliest fetal stages, with a particular focus on neural stem cells. To accomplish this, the team assembled a curated list of nearly 3,000 genes associated with neuropsychiatric disorders, neurodegenerative diseases, and cortical malformations, then simulated how alterations in these genes would affect cells involved in cortical development.
Because these prenatal stages are difficult to study directly, the researchers integrated multiple sources of data: single-cell and bulk transcriptomic datasets from human and mouse brain tissue, along with experiments in human NSCs cultivated in vitro. This combined strategy made it possible to reconstruct gene expression dynamics and the regulatory networks that operate as NSCs transition through different telencephalic fates.
Co-lead Nicola Micali, an associate researcher at Dr. Pasko Rakic’s lab at Yale University, notes that while most studies examine disease genes in adult brains, their analysis reveals that many risk genes are already active during early fetal brain formation. Disruption of these genes at that stage can alter brain development and increase the likelihood of later-life disorders.
The team simulated cell-type–specific regulatory networks to evaluate how activation or depletion of disease-linked genes modulates NSC trajectories. These simulations revealed temporal windows—specific stages of cortical development—when NSCs are particularly vulnerable to gene dysfunction, as well as spatial and cell-type dependencies for each perturbation. In short, the same genetic change can have different consequences depending on when and where it occurs during development.
Researcher Xoel Mato-Blanco emphasizes that the study covers a wide range of brain pathologies and clarifies how genes implicated in those conditions behave within neural stem cells. Identifying the most relevant developmental windows and cell types provides practical guidance for where future therapeutic efforts should be focused.
By mapping the role of individual genes across developmental timelines and cell states, this work opens avenues for early diagnostics, precision gene therapies, and personalized interventions aimed at preventing or mitigating disorders that arise from disrupted cortical development.
About this genetics, mental health, and neurodevelopment research news
Author: Marta Calsina
Source: IMIM
Contact: Marta Calsina – IMIM
Image: Image credit to Neuroscience News
Original Research: Open access. “Early developmental origins of cortical disorders modeled in human neural stem cells” by Gabriel Santpere et al., published in Nature Communications.
Abstract
Early developmental origins of cortical disorders modeled in human neural stem cells
The role of early human telencephalic development—particularly neural stem cells—in the origins of cortical disorders is not fully understood. This study examines expression dynamics of genes associated with cortical and neuropsychiatric disorders across datasets generated from human NSCs during telencephalic fate transitions, both in vitro and in vivo. The analysis identifies disease risk genes expressed in early brain organizers and maps sequential gene regulatory networks active throughout corticogenesis. These results reveal disease-specific critical phases when NSCs are most susceptible to gene dysfunction, and they highlight convergent signaling pathways across multiple conditions. Simulations of risk transcription factor depletion demonstrate spatiotemporal-dependent effects on neural cell trajectories, while single-cell transcriptomics of autism patient–derived NSCs reveal recurrent disruptions in transcription factors that control brain patterning and NSC lineage commitment. Together, these findings provide a framework to investigate human brain dysfunction at the earliest stages of development.