Dr. Muhle and her team work to understand how genetic changes in people lead to autism spectrum disorder (ASD) and other neurodevelopmental disorders. One of the ways that changes in DNA can result in widespread changes during development is by a genetic mutation referred to as a “loss of function” mutation.
People that carry a loss of function mutation in a gene critical for development of the brain may have disrupted expression or function of that gene in the brain, resulting in atypical patterns of neurodevelopment and an increased risk for ASD. One such gene is CHD8. In our preliminary studies, we have found that CHD8 binds to other ASD risk genes more often than expected by chance, and that genes targeted by CHD8 are part of a network of genes that are active during a critical period of fetal brain development. The role of CHD8 in specific cell types in the developing brain is largely unknown, however.
We used CRISPR gene editing to generate several mouse lines to explore the function of CHD8 in specific cells of the developing cortex. By collecting lists of genes that are altered by Chd8 loss of function and targeted by Chd8 in specific types of brain cells, we can examine them for overrepresentation of other ASD risk genes, a sign that those cell types are important players in the development of autism. By exploring the functions of these genes and learning what kinds of biological pathways connect these genes with each other, we can increase our knowledge of the mechanisms underlying autism and gain new insights into the origins of the disorder.