An international research team has used genome-wide CRISPR knockout screening to identify hundreds of genes required for early brain development, including one linked to a severe neurodevelopmental disorder that had not been previously described. The work, published in Nature Neuroscience, provides a systematic view of the genetic programs that guide neural differentiation and how their disruption contributes to disease.
Led by Sagiv Shifman at The Hebrew University of Jerusalem, in collaboration with Binnaz Yalcin at INSERM, the researchers asked which genes are required for embryonic stem cells to become brain cells. Using CRISPR-based gene editing, the team individually inactivated nearly 20,000 genes in embryonic stem cells and tracked the effects as the cells differentiated into neural lineages.
“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,” Shifman said.
The screen identified 331 genes essential for neuron generation, many of which had not been previously associated with early neural development. One gene, PEDS1, emerged as a key finding. The gene encodes an enzyme required for plasmalogen synthesis, a class of membrane phospholipids enriched in myelin. Loss of PEDS1 impaired neural differentiation and reduced brain size in experimental models.
Genetic analysis of two unrelated families revealed rare PEDS1 mutations in children with severe developmental delay and microcephaly. Functional experiments confirmed that PEDS1 is required for normal neuron formation and migration, linking the molecular defect to the clinical phenotype.
The study also showed that genes involved in transcriptional and chromatin regulation tend to cause dominant neurodevelopmental disorders, while metabolic genes such as PEDS1 are more often associated with recessive conditions. The researchers have made their gene essentiality data available through an open online database to support further work in neurodevelopmental genetics.
Publication Details
Amelan, A., Collins, S.C., Damseh, N.S. et al. CRISPR knockout screens reveal genes and pathways essential for neuronal differentiation and implicate PEDS1 in neurodevelopment. Nat Neurosci (2026). https://doi.org/10.1038/s41593-025-02165-0
Led by Sagiv Shifman at The Hebrew University of Jerusalem, in collaboration with Binnaz Yalcin at INSERM, the researchers asked which genes are required for embryonic stem cells to become brain cells. Using CRISPR-based gene editing, the team individually inactivated nearly 20,000 genes in embryonic stem cells and tracked the effects as the cells differentiated into neural lineages.
“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,” Shifman said.
The screen identified 331 genes essential for neuron generation, many of which had not been previously associated with early neural development. One gene, PEDS1, emerged as a key finding. The gene encodes an enzyme required for plasmalogen synthesis, a class of membrane phospholipids enriched in myelin. Loss of PEDS1 impaired neural differentiation and reduced brain size in experimental models.
Genetic analysis of two unrelated families revealed rare PEDS1 mutations in children with severe developmental delay and microcephaly. Functional experiments confirmed that PEDS1 is required for normal neuron formation and migration, linking the molecular defect to the clinical phenotype.
The study also showed that genes involved in transcriptional and chromatin regulation tend to cause dominant neurodevelopmental disorders, while metabolic genes such as PEDS1 are more often associated with recessive conditions. The researchers have made their gene essentiality data available through an open online database to support further work in neurodevelopmental genetics.
Publication Details
Amelan, A., Collins, S.C., Damseh, N.S. et al. CRISPR knockout screens reveal genes and pathways essential for neuronal differentiation and implicate PEDS1 in neurodevelopment. Nat Neurosci (2026). https://doi.org/10.1038/s41593-025-02165-0