An international team of researchers, including those from the Hebrew University, identified 331 genes critical for neuronal differentiation, and pointed to PEDS1 as a cause of a neurodevelopmental disorder.
Neurodevelopmental disorders (such as developmental delay, some cases of autism spectrum disorders, and microcephaly) often result from disruptions that occur very early in the process by which embryonic stem cells differentiate into neurons. However, there is a significant scientific challenge: the nervous system has multiple pathways, functional overlaps, and complex developmental timings, and many of the genes involved in these processes have not yet been identified. Moreover, even when a “suspect gene” is identified in genetic testing, it is difficult to prove that it actually drives the phenotype and is not a coincidental finding.
In a new study published in the journal Nature Neuroscience, an international research team led by Prof. Sagiv Shifman from the Institute of Life Sciences at the Hebrew University of Jerusalem, in collaboration with Prof. Binaz Yelchin from INSERM in France, proposes a systems approach: instead of searching for a single gene at a time, systematically mapping the genes whose presence is necessary for stem cells to successfully undergo the neuronal differentiation pathway.
Research methodology: Large-scale CRISPR screening
The research team, which includes researchers from Israel, France, and Japan, performed CRISPR screening on an unprecedented scale: purposefully turning off about 20,000 genes in mouse embryonic stem cells, and then monitoring their ability to undergo differentiation into functional neurons. This made it possible to precisely identify the "turn-offs" that cause failure in the process, and at which specific stages. The main result is the identification of 331 genes that were found to be essential for the formation of neurons, many of which had not previously been directly linked to neural differentiation.
Dominant vs. recessive pattern: mechanistic insight
One interesting scientific insight is that genes associated with dominantly inherited disorders (in which one defective copy is sufficient for disease expression) tend to be enriched in transcriptional regulatory roles—that is, roles that “manage” genetic programs in the cell. In contrast, genes associated with recessive disorders (which require two defective copies) tend to be involved in metabolic pathways. While this division does not resolve the full complexity, it does provide a conceptual framework: when a new mutation is discovered in a clinical test, one can ask whether it falls into the “managerial” or “metabolic” category, and what this indicates about the pathophysiological mechanism.
From the lab to the clinic: The story of PEDS1
The highlight of the study is the identification of a new role for the PEDS1 gene, which is involved in the production of plasmalogens—special lipids in cell membranes known to be particularly important in the nervous system and myelin. In the screen, the researchers found that PEDS1 plays an important role in the formation of nerve cells, and that its loss leads to reduced brain size.
From there, the researchers moved to the clinical phase: searching for mutations in PEDS1 in families, and identifying a rare mutation in PEDS1 in two unrelated families, in two children with a severe developmental disorder characterized by developmental delay and a smaller brain. To strengthen the causal link, the researchers turned off PEDS1 in experimental models. The experiments confirmed that PEDS1 is necessary for normal brain development, including the generation and migration of nerve cells, findings that may explain the clinical features observed in the affected children.
Prof. Sagiv Shifman from the Faculty of Mathematics and Natural Sciences at the Hebrew University explains: "By monitoring the differentiation of embryonic stem cells into nerve cells and systematically disrupting almost all genes in the genome, we have 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 as-yet-undiscovered neurodevelopmental disorders. Identifying PEDS1 as a genetic cause of developmental disability in children, and clarifying its role, opens the door to improved diagnosis and genetic counseling for families, and may ultimately support the development of targeted treatments."
"Vitality" map for distinguishing between autism and developmental delay
The team's "essentiality" map, which shows when genes are needed during development, also helped to clarify differences between the mechanisms underlying autism and developmental delay. Genes that are broadly essential were found to be more strongly associated with developmental delay, while genes that are specifically critical during stages of nerve cell formation were found to be more strongly associated with autism. This finding helps explain how disruptions in different pathways can lead to overlapping symptoms.
The Research and Accessibility to Science Team
The research included contributions from Prof. Tamar Harel, Dr. Galia Monderer-Rotkoff, Alana Amlan, Ohad Salim, and Elad Dvir from the Hebrew University, in addition to collaboration with researchers from France and Japan.
The researchers made the findings accessible by launching an open online database that includes the full results of the CRISPR screen. Prof. Schiffman attributed the initiative to doctoral student Alena Amlan: "We wanted our findings to serve the entire scientific community."
Limitations and Interpretation Considerations
It should be remembered that this is a model system (stem cells and differentiation in the laboratory, and a screen in the mouse). The human brain is more complex, and includes processes of tissue organization and long developmental timelines that are not fully reproduced in these models. Therefore, translation into clinical practice should be done with caution. However, the methodology itself “large-scale screen → candidate gene list → ranking by function → clinical validation” constitutes a template that can accelerate the discovery of new genetic causes of neurodevelopmental disorders.
More of the topic in Hayadan:
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I got it. I was indeed not quiet with the translation but now it looks better. In any case it was supposed to be SCREENING
"Screen" means "filtering"