Researchers identify hundreds of genes essential for the development of brain cells

An international research team identified hundreds of genes essential for the development of brain cells, including one gene linked to a severe neurodevelopmental disorder not previously described. The study published in Nature Neuroscience offers a new approach to identifying genes involved in neurodevelopmental disorders, including autism.

Which genes are required for turning embryonic stem cells into brain cells, and what happens when this process goes wrong? In a new study published today in Nature Neuroscience, researchers led by Prof. Sagiv Shifman from The Institute of Life Sciences at The Hebrew University of Jerusalem, in collaboration with Prof. Binnaz Yalcin from INSERM, France, used genome-wide CRISPR knockout screens to identify genes that are needed for early brain development.

Extensive genetic mapping of genes involved in early brain development

The study set out to answer a straightforward question: which genes are required for the proper development of brain cells?

Using CRISPR-based gene-editing methods, the researchers systematically and individually "switched off" roughly 20,000 genes to study their role in brain development. They performed the screen in embryonic stem cells and while the cells changed into brain cells. By disrupting genes one by one, the team could see which genes are required for this transition to proceed normally.

Using this approach, the team mapped key steps in neural differentiation and identified 331 genes that are essential for generating neurons. Many of these genes had not previously been linked to this process, and the findings may help clarify the genetic basis of neurodevelopmental conditions, including altered brain size, autism, and developmental delay.

New clinical and mechanistic discovery: the PEDS1 gene

One of the study's central findings is the identification of PEDS1 as the cause of a previously undescribed neurodevelopmental disorder.

PEDS1 is required for the production of plasmalogens, a specialized class of membrane phospholipids that are enriched in myelin, the fatty sheath that insulates nerve fibers. In their genetic screen, the researchers also found that PEDS1 plays an important role in nerve cell formation and that its loss leads to reduced brain size. Based on these results, the team hypothesized that PEDS1 deficiency could also disrupt human brain development.

Genetic testing in two unrelated families identified a rare PEDS1 mutation associated with a severe developmental disorder in two children, marked by developmental delay and a smaller brain.

To test causality, the researchers inactivated PEDS1 in experimental models. These experiments confirmed that PEDS1 is essential for normal brain development, including the generation and migration of nerve cells, findings that may help explain the clinical features observed in the affected children.

Prof. Sagiv Shifman of the Faculty of Mathematics and Natural Sciences at Hebrew University explains: "By tracking the differentiation of embryonic stem cells into neural cells and systematically disrupting nearly all genes in the genome, we created a map of the genes essential for brain development. This map can help us better understand how the brain develops and identify genes linked to neurodevelopmental disorders that have yet to be discovered. Identifying PEDS1 as a genetic cause of developmental impairment in children, and clarifying its function, opens the door to improved diagnosis and genetic counseling for families, and may eventually support the development of targeted treatments."

Additional discoveries

The researchers found that inheritance patterns in neurodevelopmental syndromes may be predicted by the biological pathways involved. For genes that regulate other genes, such as those involved in regulating transcription and chromatin, disorders are often dominant, meaning a mutation in just one copy of the gene can be enough to cause disease. By contrast, disorders linked to metabolic genes (including PEDS1) are often recessive and require mutations in both copies of the gene, typically with each parent carrying one altered copy. This relationship between the biological pathway and inheritance could help clinicians and researchers recognize and prioritize candidate disease genes.

The team's "essentiality map," which shows when genes are required during development, also helped clarify differences between the mechanisms underlying autism and developmental delay. Genes that are broadly essential were more strongly associated with developmental delay, while genes that are specifically critical during the stages of nerve cell formation were more strongly associated with autism. This helps explain how disruptions in different pathways can lead to overlapping symptoms and supports the view that changes in early brain development can contribute to autism.

The research was supported by the Israel Science Foundation (ISF), the ISF–Broad Institute Program, and the MAVRI Biomedical Research Program.

To help advance neurodevelopmental research, the team has also launched an open online database that includes the experiment's results, making the data accessible to researchers worldwide.

Prof. Shifman added: "This was an excellent idea from PhD student Alana Amelan, who carried out a large part of the study and also created the website. We wanted our findings to serve the entire scientific community, supporting ongoing work on the genes we identified and helping researchers pinpoint additional genes involved in neurodevelopmental disorders."

The study provides a comprehensive map of genes involved in early nervous system development and highlights molecular mechanisms underlying a developmental disorder that affects the developing brain.

These insights may improve genetic diagnosis of neurodevelopmental disorders and help lay the groundwork for medical research into new approaches to prevention and treatment.