Document Type
Article
Publication Date
4-5-2024
Original Citation
Cortes D,
Escudero M,
Korgan A,
Mitra A,
Edwards A,
Aydin S,
Munger SC,
Charland K,
Zhang Z,
O'Connell K,
Reinholdt L,
Pera M.
An in vitro neurogenetics platform for precision disease modeling in the mouse. Sci Adv. 2024;10(14):eadj9305.
Keywords
JMG, Animals, Mice, Humans, Pluripotent Stem Cells, Phenotype
JAX Source
Sci Adv. 2024;10(14):eadj9305.
ISSN
2375-2548
PMID
38569042
DOI
https://doi.org/10.1126/sciadv.adj9305
Grant
his work was supported by the Jackson laboratory. d.e.C. was the recipient of a JAX Scholar award. A.e. was a participant in the JAX Summer Student Program. A national institutes of health grant to l.G.R. (U42 Od010921) supported meSC derivation and expansion.
Abstract
The power and scope of disease modeling can be markedly enhanced through the incorporation of broad genetic diversity. The introduction of pathogenic mutations into a single inbred mouse strain sometimes fails to mimic human disease. We describe a cross-species precision disease modeling platform that exploits mouse genetic diversity to bridge cell-based modeling with whole organism analysis. We developed a universal protocol that permitted robust and reproducible neural differentiation of genetically diverse human and mouse pluripotent stem cell lines and then carried out a proof-of-concept study of the neurodevelopmental gene DYRK1A. Results in vitro reliably predicted the effects of genetic background on Dyrk1a loss-of- function phenotypes in vivo. Transcriptomic comparison of responsive and unresponsive strains identified molecular pathways conferring sensitivity or resilience to Dyrk1a1A loss and highlighted differential messenger RNA isoform usage as an important determinant of response. This cross-species strategy provides a powerful tool in the functional analysis of candidate dis- ease variants identified through human genetic studies.
Comments
Copyright © 2024 the Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. no claim to original U.S. Government Works. distributed under a Creative Commons Attribution nonCommercial license 4.0 (CC BY- nC).