Neurodevelopmental disorders can result from mutations in genes essential for brain development. However, we still lack fundamental knowledge about the genes and pathways crucial for this highly regulated process. In my current work, I study genes implicated in neurodevelopmental processes using genome-wide CRISPR screens. We conducted the first genome-wide CRISPR screen for genes essential for neural differentiation. Our study reveals novel genes and pathways essential for this process. We characterized the in vivo effects of mutations in eight genes on the anatomy of the mouse brain, showing the neuroanatomical impact of neural differentiation, notably at the tissue size level. Our work is unique because most functional studies focus on one or a few genes, while our study spans the entire coding genome. This has enabled us to discover a unique pattern among autism genes, distinguishing them from genes involved in developmental delay. Additionally, unlike naturally occurring mutations, our approach induces mutations in both alleles, enabling the identification of both dominant and recessive genes simultaneously. This approach has led to the novel finding that dominant and recessive neurodevelopmental disorders are mainly associated with distinct gene pathways. Demonstrating the translational potential of our approach, we identified bi-allelic loss-of- function variants in the PEDS1 gene implicated in a novel human neurodevelopmental syndrome. PEDS1 mediates the final step in plasmalogen biosynthesis. Plasmalogens are poorly studied but constitute 15-20% of total phospholipids in mammalian cell membranes and more in the brain. Currently, I am studying the role of Peds1 in neuronal differentiation and migration.

Supervisor: Prof. Sagiv Shifman