Organ System/Disease Focus
Neurodevelopmental and neurodegenerative disorders, brain, cerebellum, autism, ARSACS
Aligned Research Focus
Neuronal development modelled using iPSCs
Biography
Member of the SCRMC Neural Regeneration Focus Group
Research Description:
Genetic diversity shapes every human phenotype. This includes everyday traits such as cognition and brain structure, as well as risk for neurological and neurodevelopmental disease. Currently the most powerful tool for connecting regions of the genome to specific traits is the genome wide association study (GWAS), which correlates millions of genetic variants to a trait of interest in thousands of human participants. GWAS has revealed how genetics affects many disorders of the brain, but results are often difficult to interpret, and do not inherently explain the mechanism by which genetics affects the brain. To fill this gap, we are developing novel approaches to study genetic variation in libraries of genetically diverse iPSC lines, which can be differentiated into most cell types of the brain. Our goal is to identify, and mechanistically explore, genetic modifiers of neurodevelopmental disorders. Specifically, we focus on the maturation and assymetric cell divisions of neural progenitor cells, and how patterns of proliferation affects the fate of daughter cells. These insights may provide deeper understanding of the heterogeneity in disease outcomes, and can be leveraged to test therapeutic hypotheses.
Selected References:
1. Wolter, J.M.*, Le, B.D.*, Matoba, N., Lafferty, M.J., Aygün, N., Liang, D., Courtney, K., Elwell, A., Piven, J., Zylka, M.J., Stein, J. “Cellular GWAS identifies common genetic variants that influence lithium induced neural progenitor proliferation.” Biological Psychiatry (2023)
2. Matoba, N.*, Le, B.D.*, Valone, J.M.*, Wolter, J.M., Mory, J., Liang, D., Aygün, N., Liang, D., Boradaway, K.A., Bond, M., Mohlke, K.L., Zylka, M.J., Love, M.I., Stein, J. “WNT activity reveals context-specific genetic effects on gene regulation in neural progenitors.” bioRxiv (2023).
3. Liang, D., Elwell, A.L., Aygün, N., Krupa, O., Wolter, J.M., Kyere, F.A., Lafferty, M.J., Cheek, K.E., Courtney, K.P., Yusupova, M., Garrett, M.E., Ashley-Koch, A., Crawford, G.E., Love, M.I., de la Torre-Ubieta, L., Geschwind, D.H., Stein, J.L. “Cell-type specific effects of genetic variation on chromatin accessibility during human neuronal differentiation.” Nature Neuroscience (2021)