Understanding brain development and maintenance via spatial transcriptomics
Project Overview
We identified changes in the gene called IRF2BPL (Interferon Regulatory Factor 2 Binding Protein Like) as the cause of a severe brain disorder in children called NEDAMSS (Neurodevelopmental disorder with abnormal movements, loss of speech and seizures). Children with NEDAMSS show typical early development followed by severe symptoms (movement problems, seizures, loss of speech) that occur at around five years old. NEDAMSS has no treatment or cure. Other changes in this same gene, IRF2BPL, are associated with autism spectrum disorder (ASD), and IRF2BPL is considered a top, clinically relevant ASD gene. We know that IRF2BPL is expression is high in the cerebral cortex. It is located in the nucleus and likely regulates thousands of genes. We have generated the first Irf2bpl gene knockout mice that, like humans, display movement problems. We have also made patient-derived knock-in mice reflecting a recurring change in IRF2BPL. We want to use these mice to find out what genes, cell types and locations are misregulated upon loss of Irf2bpl within the mouse cortex. Importantly, we will take advantage of the recent CFI-funded infrastructure at the University of Manitoba to conduct state-of-the-art spatial transcriptomics. These experiments will allow us to accurately determine what genes are misregulated in the cortex when Irf2bpl is lost or changed. This is important as different cell types could respond differently to the loss of Irf2bpl and may highlight the key cells and locations to target therapeutically. This novel work will be critical to understanding the role of IRF2BPL gene regulation and the alterations that contribute to disease pathogenesis.
Principal Investigator
Paul Marcogliese , The University of Manitoba