An international research team has identified hundreds of genes essential for early brain development, revealing new insights into how neurons form—and what happens when this process fails. Published in Nature Neuroscience, the study introduces a powerful genome-wide approach to uncovering genes involved in neurodevelopmental disorders, including autism and developmental delay.
Led by Prof. Sagiv Shifman at The Hebrew University of Jerusalem in collaboration with Prof. Binnaz Yalcin (INSERM, France), the researchers combined CRISPR knockout screening with stem cell biology to build one of the most comprehensive genetic maps of early brain development to date.
🧬 Mapping the Genes That Build the Brain #
The central question of the study was deceptively simple: Which genes are required to turn embryonic stem cells into brain cells?
To answer it, the team used genome-wide CRISPR gene editing to systematically disable nearly 20,000 genes, one by one. They performed these knockouts both in embryonic stem cells and during their differentiation into neural cells, allowing them to observe which genetic disruptions blocked or altered normal brain-cell development.
This approach enabled the researchers to trace key stages of neural differentiation and identify 331 genes that are essential for generating neurons. Many of these genes had not previously been associated with early brain development.
The findings provide a clearer genetic framework for understanding disorders characterized by altered brain size, autism spectrum features, and developmental delay.
🧠 PEDS1: A Newly Identified Neurodevelopmental Disorder Gene #
One of the most significant discoveries of the study is the identification of PEDS1 as the cause of a previously undescribed neurodevelopmental disorder.
PEDS1 is required for the synthesis of plasmalogens, a specialized class of membrane phospholipids that are especially abundant in myelin, the insulating layer surrounding nerve fibers. In the CRISPR screen, loss of PEDS1 impaired neuron formation and led to reduced brain size in experimental models.
Based on these findings, the researchers hypothesized that PEDS1 deficiency might also affect human brain development. Genetic testing in two unrelated families confirmed this link, identifying rare PEDS1 mutations in children with severe developmental delay and microcephaly.
Follow-up experiments in model systems showed that inactivating PEDS1 disrupts:
- Neuron generation
- Neuronal migration
- Overall brain growth
These results establish PEDS1 as a critical gene for normal brain development and explain the clinical features observed in affected patients.
🧪 Inheritance Patterns Reveal Biological Logic #
Beyond identifying individual genes, the study uncovered a broader principle: inheritance patterns in neurodevelopmental disorders often reflect the biological pathways involved.
- Genes that regulate other genes—such as those controlling transcription or chromatin structure—are more likely to cause dominant disorders, where a mutation in just one gene copy is sufficient.
- Metabolic genes, including PEDS1, tend to cause recessive disorders, requiring mutations in both gene copies.
This relationship between molecular function and inheritance provides clinicians and researchers with a valuable framework for prioritizing candidate disease genes during diagnosis and genetic analysis.
🧩 Distinguishing Autism from Developmental Delay #
The team’s “essentiality map”—which tracks when genes are required during development—also helped clarify differences between autism and developmental delay at a mechanistic level.
- Broadly essential genes, required across many developmental stages, showed stronger associations with developmental delay.
- Genes that are specifically critical during neuron formation were more strongly linked to autism.
This distinction helps explain why these conditions often share overlapping symptoms while arising from disruptions in different biological pathways. It also reinforces the idea that early brain development is a key window during which genetic disruptions can shape long-term neurological outcomes.
🌍 Open Data for the Scientific Community #
To accelerate progress in neurodevelopmental research, the team launched an open online database containing the full results of their CRISPR screen. The resource allows researchers worldwide to explore gene essentiality across developmental stages and identify new candidate genes linked to brain disorders.
Prof. Shifman emphasized the collaborative intent behind the project, noting that the idea for the database came from PhD student Alana Amelan, who played a central role in both the experimental work and the creation of the platform.
🔍 Why This Research Matters #
This study delivers:
- A comprehensive genetic map of early brain development
- Identification of 331 neuron-essential genes
- Discovery of PEDS1 as a cause of a severe neurodevelopmental disorder
- New insight into how genetic pathways shape inheritance and disease outcomes
By combining large-scale CRISPR screening with clinical genetics, the work bridges basic neuroscience and human disease. These insights are expected to improve genetic diagnosis, inform genetic counseling, and lay the groundwork for future research into targeted therapies for neurodevelopmental disorders.
As Prof. Shifman summarized, understanding how the brain is built—gene by gene—offers one of the most promising paths toward understanding how neurodevelopmental disorders arise, and how they might one day be treated.