Wong, Jasmine C, Perez-Mancera, Pedro A, Huang, Tannie Q, Kim, Jangkyung, Grego-Bessa, Joaquim, Alzamora, Maria del Pilar, Kogan, Scott C, Sharir, Amnon, Keefe, Susan H, Morales, Carolina E et al (show 10 more authors)
(2020)
Kras<SUP>P34R</SUP> and Kras<SUP>T58I</SUP> mutations induce distinct RASopathy phenotypes in mice.
JCI INSIGHT, 5 (21).
140495-.
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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Animals, Mice, Inbred C57BL, Mice, Craniosynostoses, Lung Diseases, Cardiomyopathies, Hematologic Diseases, Pregnancy, Mutation, Female, Male, Proto-Oncogene Proteins p21(ras) |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 12 Jul 2021 09:46 |
| Last Modified: | 14 Oct 2023 15:34 |
| DOI: | 10.1172/jci.insight.140495 |
| Open Access URL: | https://doi.org/10.1172/jci.insight.140495 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3129718 |
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