Grant: Project Grant

Our genes are arranged on large pieces of DNA called chromosomes. The chromosomes are huge molecules that must undergo multiple levels of compaction to fit into the cell. At the same time, the genes characteristic of that cell type must remain accessible for activation. In a stem cell the chromosomes are loosely packaged and many genes are poised for activation. When the stem cell commits to becoming a specific cell type (eg. neuron) it must tightly package and silence those genes that are not required and fully activate those genes that will be turned on. To manage this process cells have developed a complex series of proteins to control the structure of chromosomes and the regulation of genes. When this process is defective, cells cannot divide, differentiate or initiate gene expression effectively. Indeed, recent work has shown that mutations in chromosome regulating proteins cause a variety of human diseases, including developmental disorders with severe intellectual disability and autism. This project studies the ATRX gene that, when mutated, causes intellectual disability and autism spectrum disorder (ASD). The prevailing theory for these complex disorders is that an early developmental process is altered and that this subsequently affects neuronal connections leading to altered wiring of the brain and compromised cognitive skills. Despite our success in identifying these genes, our understanding of how these chromosome regulatory proteins coordinate which genes to turn on or off, when to turn them on or off, and how that leads to altered wiring remains poorly defined. This project aims to use a mouse inactivated for ATRX to define its role during the formation of the entorhinal cortex (EC) and how it connects to the hippocampus (HP). The EC-HP circuit is critical for complex learning tasks such as spatial navigation maps. A thorough understanding of the formation of this circuit will provide insight into the etiology of ASD.