The mouse is often the model of choice for genetic analysis of neurological disorders, but the introduction of disease mutations into a single inbred strain sometimes fails to yield phenotypes relevant to human disease. Interrogating genetically diverse panels of mice can identify better models of human sensitivity and resistance to candidate disease variants. We developed an in vitro methodology for modeling multiple stages of central nervous system development using a panel of genetically diverse mouse embryonic stem cell lines. Chemical knockdown of the neurodevelopmental gene Dyrk1a demonstrated profound strain differences in the cellular response to the ablation of DYRK1A activity throughout development in vitro. Responsive strains showed in vitro developmental defects consistent with observations in vivo on Dyrk1a knockout mice, and transcriptomic analysis of sensitive and resistant cell strain backgrounds successfully identified key molecular pathways in neural development known to be associated with Dyrk1a haploinsufficiency in vivo. Thus, we demonstrate that high throughput comparative phenotype analysis of differentiated cells from human and genetically diverse mouse pluripotent stem cells bearing disease mutations can provide a facile route to identification of optimal mouse strains for precision disease modeling in vivo.
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