Genes linked to brain development revealed by CRISPR genome editing

A large-scale study has unveiled genes essential for early brain development and uncovered the cause of a previously unrecognised neurodevelopmental disorder. 

Researchers used CRISPR-based genome-editing to individually knock out (remove or disable) approximately 20,000 genes in mouse embryonic stem cells, creating a map of the genes guiding differentiation into neurons. The study, published in Nature Neuroscience, charts the major stages of neural differentiation, which is essential for brain and nervous system development, and sheds light on the genetic roots of neurodevelopmental conditions.  

Professor Sagiv Shifman from the Institute of Life Sciences at the Hebrew University of Jerusalem, Israel 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 researchers identified 331 genes that are required for normal neuron formation, including many not previously associated with early brain development. One of these genes, PEDS1, was pinpointed as the cause of a previously unrecognised neurodevelopmental disorder.

The PEDS1 protein is essential for the production of plasmalogens, a type of membrane phospholipid especially abundant in the myelin sheaths that insulate neurons. The researchers found that knocking out the gene in mouse models resulted in a smaller brain size, which they hypothesised may also indicate a role in human brain development.

To test this hypothesis, two unrelated families with children who had severe developmental symptoms underwent genetic testing, revealing rare PEDS1 mutations. To establish causality, the researchers then showed that shutting down PEDS1 in a mouse model causes neurons to fail to form and migrate properly.  

Professor Shifman said: 'Identifying PEDS1 as a genetic cause of developmental impairment in children, and clarifying its function, opens the door to improved diagnosis and genetic counselling for families, and may eventually support the development of targeted treatments.' 

The study also revealed broader patterns of neurodevelopmental disorders. Genes involved in regulating other genes, such as controlling transcription or chromatin, are often linked to dominant disorders, in which only one faulty copy results in symptoms. In contrast, disorders connected to metabolic genes, such as PEDS1, tend to be recessive, meaning that two faulty copies of the gene are necessary for symptoms to develop. 

The researchers created a map cataloguing when each gene is needed during neuronal development, which they hope will help to discern differences between autism and developmental delay at a biological level. They discovered that genes essential across many developmental stages appear to be involved in developmental delay, whereas genes especially important during the formation of nerve cells seem more closely associated with autism. 

The team has launched an open online database allowing their genetic map of early nervous system development to be available to other researchers.

Professor Shifman said: '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.'