An international research team led by Prof. Sagiv Shifman of the Hebrew University of Jerusalem identified hundreds of genes essential for the development of brain cells, including one linked to a previously unknown severe neurodevelopmental disorder. Published in Nature Neuroscience, the study used genome-wide CRISPR [based gene-editing] knockout screens to reveal which genes drive the transformation of embryonic stem cells into brain cells, and what happens when this process goes wrong, offering a new approach to studying disorders such as autism.
Genetic mapping of 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, the researchers systematically and individually “switched off” roughly 20,000 genes to study their role in brain development as embryonic stem cells transformed into brain cells. By disrupting genes one by one, the team identified 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 was 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 enriched in myelin, the fatty sheath that insulates nerve fibers. The researchers also found that PEDS1 plays an important role in nerve cell formation and that its loss leads to reduced brain size. 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, confirming that it is essential for normal brain development, including the generation and migration of nerve cells.
The researchers also found that inheritance patterns in neurodevelopmental syndromes may be predicted by the biological pathways involved. Genes involved in transcription and chromatin regulation were more often linked to dominant disorders, while metabolic genes, including PEDS1, were more often associated with recessive disorders. The team’s “essentiality map,” showing when genes are required during development, also helped clarify differences between autism and developmental delay. Genes that are broadly essential were more strongly associated with developmental delay, while genes specifically critical during nerve cell formation were more strongly associated with autism.
Prof. Shifman said: “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.”
The study provides a comprehensive map of genes involved in early nervous system development and may improve genetic diagnosis of neurodevelopmental disorders while laying the groundwork for new approaches to prevention and treatment.
The research paper titled “CRISPR knockout screens reveal genes and pathways essential for neuronal differentiation and implicate PEDS1 in neurodevelopment” is now available in Nature Neuroscience, and can be accessed at here.
For a century, the Hebrew University of Jerusalem has been a beacon for visionary minds who challenge convention and shape the future. Founded by luminaries like Albert Einstein, who entrusted his intellectual legacy to the university, it is dedicated to advancing knowledge, cultivating leadership, and promoting diversity. Home to over 23,000 students from 90 countries, the Hebrew University drives much of Israel’s civilian scientific research and the commercialization of technologies through Yissum, its tech transfer company. Hebrew University’s groundbreaking contributions have been recognized with major international awards, including ten Nobel Prizes, two Turing Awards, and a Fields Medal. Ranked 88th globally by the Shanghai Ranking (2025), Hebrew University marks a century of excellence in research, education, and innovation. To learn more about the university’s academic programs, research, and achievements, visit the official website at http://new.huji.ac.il/en.