1. KrasP34R and KrasT58I mutations induce distinct RASopathy phenotypes in mice
- Author
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Wong, Jasmine C, Perez-Mancera, Pedro A, Huang, Tannie Q, Kim, Jangkyung, Grego-Bessa, Joaquim, del pilar Alzamora, Maria, Kogan, Scott C, Sharir, Amnon, Keefe, Susan H, Morales, Carolina E, Schanze, Denny, Castel, Pau, Hirose, Kentaro, Huang, Guo N, Zenker, Martin, Sheppard, Dean, Klein, Ophir, Tuveson, David, Braun, Benjamin S, and Shannon, Kevin
- Subjects
Biomedical and Clinical Sciences ,Pediatric ,Lung ,Cancer ,Rare Diseases ,Genetics ,Aetiology ,2.1 Biological and endogenous factors ,Animals ,Cardiomyopathies ,Craniosynostoses ,Female ,Hematologic Diseases ,Lung Diseases ,Male ,Mice ,Mice ,Inbred C57BL ,Mutation ,Pregnancy ,Proto-Oncogene Proteins p21(ras) ,Genetic diseases ,Mouse models ,Signal transduction ,Biomedical and clinical sciences ,Health sciences - Abstract
Somatic KRAS mutations are highly prevalent in many cancers. In addition, a distinct spectrum of germline KRAS mutations causes developmental disorders called RASopathies. The mutant proteins encoded by these germline KRAS mutations are less biochemically and functionally activated than those in cancer. We generated mice harboring conditional KrasLSL-P34Rand KrasLSL-T58I knock-in alleles and characterized the consequences of each mutation in vivo. Embryonic expression of KrasT58I resulted in craniofacial abnormalities reminiscent of those seen in RASopathy disorders, and these mice exhibited hyperplastic growth of multiple organs, modest alterations in cardiac valvulogenesis, myocardial hypertrophy, and myeloproliferation. By contrast, embryonic KrasP34R expression resulted in early perinatal lethality from respiratory failure due to defective lung sacculation, which was associated with aberrant ERK activity in lung epithelial cells. Somatic Mx1-Cre-mediated activation in the hematopoietic compartment showed that KrasP34R and KrasT58I expression had distinct signaling effects, despite causing a similar spectrum of hematologic diseases. These potentially novel strains are robust models for investigating the consequences of expressing endogenous levels of hyperactive K-Ras in different developing and adult tissues, for comparing how oncogenic and germline K-Ras proteins perturb signaling networks and cell fate decisions, and for performing preclinical therapeutic trials.
- Published
- 2020