A new study led by scientists from the Hebrew University of Jerusalem and INSERM identified genes essential for turning embryonic stem cells into brain cells, including a gene linked to a previously undescribed neurodevelopmental disorder. Full details are provided in Nature Neuroscience in a paper aptly titled “CRISPR knockout screens reveal genes and pathways essential for neuronal differentiation and implicate PEDS1 in neurodevelopment.”
According to the paper, the scientists used CRISPR-based gene editing to systematically and individually switch off the roughly 20,000 genes in mouse embryonic stem cells and assess how they affected brain development. Disrupting genes one by one, let the team see which genes were necessary for the stem cell to brain cell transition to proceed normally. Their approach enabled them to map key steps in the neural differentiation, including identifying 331 genes that are crucial for neuronal generation, many of which, they noted, have not been linked to this process before.
One of the central findings of the study was the link between changes in PEDS1 and a previously undescribed neurodevelopmental disorder. In the body, PEDS1 plays a role in producing plasmalogens, a class of myelin-enriched membrane phospholipids. The team’s analysis of edits to PEDS1 showed that its loss resulted in reduced brain size, leading them to hypothesize that people deficient in this gene could have disruptions in brain development. In fact, previous genetic testing in two unrelated families identified a rare PEDS1 mutation in two children with a severe neurodevelopmental disorder with developmental delays and a smaller brain size.
To confirm their hypothesis, the scientists inactivated PEDS1 in mouse models and observed the effects. Their experiments confirmed that PEDS1 is indeed essential for normal brain development, including the generation and migration of nerve cells, according to the paper. Specifically, “in mice, Peds1 deficiency led to accelerated cell-cycle exit and impaired neuronal differentiation and migration,” the scientists wrote.
Other discoveries reported in the paper include details of how inheritance patterns in neurodevelopmental syndromes may be predicted by the biological pathways involved. For example, disorders linked to regulatory genes, such as those involved in regulating transcription and chromatin, are often dominant, meaning a mutation in just one copy of the gene can be enough to cause disease. In contrast, disorders linked to metabolic genes like 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 prioritize candidate disease genes for disorders they are trying to treat.
Furthermore, the findings help clarify differences between the mechanisms underlying autism and developmental delay. Genes that are broadly essential were more strongly associated with developmental delays, while genes that are critical during 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.
Genetic maps like this “can help us better understand how the brain develops and identify genes linked to neurodevelopmental disorders that have yet to be discovered,” said Sagiv Shifman, PhD, a professor of neurogenetics at Hebrew University. “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.”
