How do embryonic stem cells become brain cells, and which genes make that transformation possible? A new study published on January 5 in Nature Neuroscience tackles this question using powerful gene editing tools. The research was 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. The team used genome-wide CRISPR knockout screens to identify the genes that are essential during the earliest stages of brain development.
The researchers began with a clear goal: to determine which genes are necessary for brain cells to form correctly.
Using CRISPR gene-editing technology, they individually disabled nearly 20,000 genes and observed what happened as embryonic stem cells attempted to become brain cells. The experiments were conducted both in stem cells and during their transformation into neural cells. By turning off genes one at a time, the scientists could pinpoint which ones were required for the process to unfold normally.
This systematic approach allowed the team to outline the major steps of neural differentiation. In total, they identified 331 genes that are critical for producing neurons. Many of these genes had not previously been associated with early brain development. The results provide new insight into the genetic factors that may contribute to neurodevelopmental conditions, including changes in brain size, autism, and developmental delay.
Identifying a New Gene Linked to Brain Disorders
Among the most significant findings was the discovery that a gene called PEDS1 is responsible for a previously unknown neurodevelopmental disorder.
PEDS1 is needed to produce plasmalogens, a specific type of membrane phospholipid that is especially abundant in myelin, the fatty coating that insulates nerve fibers. The CRISPR screen revealed that PEDS1 also plays a key role in forming nerve cells and that losing the gene results in reduced brain size. Based on these observations, the researchers proposed that a lack of PEDS1 could interfere with brain development in humans.
That idea was supported by genetic testing in two unrelated families. In both cases, children with severe developmental symptoms were found to carry a rare mutation in PEDS1. The affected children showed developmental delay along with a smaller brain.
Confirming the Role of PEDS1 in Brain Formation
To determine whether PEDS1 loss directly causes these effects, the researchers turned to experimental models and disabled the gene. These tests confirmed that PEDS1 is required for normal brain development. Without it, nerve cells do not form or migrate properly. These findings help explain the clinical features observed in the children carrying the mutation.
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.”
How Gene Function Shapes Inheritance Patterns
The study also revealed broader trends that may help predict how neurodevelopmental disorders are inherited. Genes that control the activity of other genes, including those involved in transcription and chromatin regulation, are often linked to dominant disorders. In these cases, a mutation in just one copy of the gene can be enough to cause disease.
In contrast, conditions tied to metabolic genes, including PEDS1, are more often recessive. This means that both copies of the gene must be altered, usually with each parent carrying one changed copy. Recognizing how biological pathways relate to inheritance patterns could help researchers and clinicians identify and prioritize disease related genes.
New Clues About Autism and Developmental Delay
The researchers also created an “essentiality map” showing when specific genes are required during development. This map helped distinguish between the genetic mechanisms linked to autism and those linked to developmental delay.
Genes that are essential across many stages of development were more strongly connected to developmental delay. Meanwhile, genes that are especially important during the formation of nerve cells were more closely associated with autism. These findings help explain why different genetic disruptions can lead to overlapping symptoms and support the idea that early changes in brain development can contribute to autism.
Open Data for the Research Community
The research was supported by the Israel Science Foundation (ISF), the ISF-Broad Institute Program, and the MAVRI Biomedical Research Program.
To support future discoveries, the team has launched an open online database that contains the results of the study, allowing researchers around the world to explore the data:
https://aa-shifman.shinyapps.io/Neuro_Diff_Screen/
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.”
A Foundation for Future Brain Research
Overall, the study delivers a detailed genetic map of early nervous system development and sheds light on the molecular basis of a newly identified brain disorder.
These findings may improve genetic diagnosis for neurodevelopmental conditions and help guide future research aimed at prevention and treatment.