Key Questions Answered:
Q: When do genes linked to mental illness begin to affect the brain?
A: Many genes associated with neuropsychiatric and neurodegenerative diseases are activated in the early stages of fetal brain development, much earlier than previously thought.
Question: How did researchers discover this early genetic activity?
A: By simulating the effects of nearly 3,000 disease-related genes on embryonic brain stem cells using data from human and mouse brains and in vitro models, the researchers were able to determine when and where these genes influence the brain development process.
Q: Why is this discovery important for treatment?
A: Understanding which genes act on specific cell types and during development could lead to more precise and personalized treatments targeting the underlying causes of brain and neurological diseases.
Summary: A major study has revealed that genes linked to brain and neurodegenerative disorders such as autism, depression and Parkinson’s disease affect brain development early in the fetus. These genes are active in neural stem cells (brain precursor cells) long before symptoms appear.
By combining data from humans and mice with cell models developed in the laboratory, the researchers were able to map the behavior of these genes at different developmental stages and brain cell types. This opens up new possibilities for early diagnosis, gene therapy, and targeted treatments for diseases previously thought to develop later in life.
Important facts:
- Primary source: Important disease-related genes are active in embryonic neural stem cells.
- Wide range of diseases: Genes associated with autism, schizophrenia, Alzheimer’s disease, and other diseases show early activation.
- Therapeutic potential: The results could serve as the basis for early interventions and gene-specific therapies.
Source: IMIM
Some neuropsychiatric conditions such as autism, bipolar disorder, and depression as well as neurodegenerative diseases like Alzheimer’s and Parkinson’s, may have their roots in the earliest stages of brain development before birth. During this critical period, the fetal brain undergoes rapid growth and complex wiring of neural circuits, making it highly sensitive to genetic influences, environmental exposures, and maternal health factors. Even subtle disruptions at this stage can set the stage for changes in brain structure and function that may not manifest until years or even decades later.
Researchers are increasingly uncovering how prenatal events from maternal stress and infections to nutritional deficiencies and toxin exposure can leave lasting imprints on the developing brain. These early influences may alter neural connectivity, immune responses, and neurotransmitter systems, creating vulnerabilities that interact with later life experiences. Understanding these origins not only deepens our insight into the biology of these disorders but also opens the door to preventive strategies that could begin as early as pregnancy.
This is earlier than expected, according to a study published in Nature Communications by the Hospital Del Mar Research Institute and Yale University.
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 — a joint initiative with Pompeu Fabra University — explains that the study aimed to uncover the origins of brain disorders during the earliest stages of embryonic development, focusing in particular on brain stem cells.
To do this, they used a list of nearly 3,000 genes associated with neuropsychiatric disorders, neurodegenerative pathologies, and cortical dysfunction and simulated the effects of their mutation on cells involved in brain development.
The results suggest that many of these genes are already active in the early stages of embryonic development in the formation of stem cells, brain precursor cells, and neurons and their supporting structures.
Achieving this goal was no easy task. This stage of brain development is notoriously difficult to study. So, the researchers combined data from human and mouse brains, as well as in vitro cell models.
Dr. Nicola Micali, a research associate in Dr. Pasko Rakic’s Yale University lab and co-leader of this study, explains: “Scientists typically study genes for brain disorders in adults, but in this study, we found that many of these genes are active in the early stages of fetal brain development and that they disrupt brain disorders and disrupt brain development later on.”
The study replicated regulatory networks specific to each cell type involved in brain development. This allowed the researchers to observe how activating or deactivating the analyzed genes associated with different brain diseases affected progenitor cells at different stages. This made it possible to observe the importance of each individual gene in the development of the changes that cause different diseases.
The list ranges from microcephaly and hydrocephalus to autism, depression, bipolar disorder, anorexia and schizophrenia, as well as Alzheimer’s and Parkinson’s.
All of these pathologies involve genes involved in the early stages of brain development when neural stem cells function.
“We cover a wide range of brain diseases and study how genes involved in these diseases behave in neural stem cells,” says Xoel Mato-Blanco, a researcher at the Hospital del Mar Research Institute.
At the same time, he explains that this work “identifies the time windows and cell types in which the effect of these genes is most relevant and provides clues as to when and where the function of these genes should be targeted.”
This information is “useful for understanding the origin of diseases of the cerebral cortex, that is, how genetic changes are reflected in these pathologies,” explains Dr. Santperi.
Understanding these mechanisms and the role of each gene in each disease could help develop targeted therapies that target these mechanisms and open up the possibilities of gene therapy and personalized treatment.
Abstract
“Exploring how cortical diseases arise during early development through human neural stem cell modelling”.
The importance of the early stages of human telencephalon development, which include neural stem cells (NSCs), for the etiology of cortical diseases is still unclear.
Here, we investigate the expression dynamics of genes associated with cortical and neuropsychiatric disorders in datasets generated from human neural stem cells with telencephalic fat transition in vitro and in vivo.
We identified risk genes active during corticogenesis within key brain regulators and sequential gene regulatory networks, revealing distinct critical stages at which neural stem cells may be especially vulnerable to genetic disruptions and shared signaling pathways across multiple diseases.
Furthermore, we simulated the effects of risk transcription factor (TF) deficiency on the speed of neuronal cells undergoing human corticogenesis and observed a spatiotemporal effect for each perturbation.
Finally, single-cell transcriptomics of neural stem cells derived in vitro from autism patients reveals recurrent changes in the expression of TFs that orchestrate brain pattern formation and neural stem cell lineage commitment.
This work opens new avenues for investigating human brain dysfunction in early development.
