| First Author | Wong JC | Year | 2020 |
| Journal | JCI Insight | Volume | 5 |
| Issue | 21 | PubMed ID | 32990679 |
| Mgi Jnum | J:296368 | Mgi Id | MGI:6469947 |
| Doi | 10.1172/jci.insight.140495 | Citation | Wong JC, et al. (2020) KrasP34R and KrasT58I mutations induce distinct RASopathy phenotypes in mice. JCI Insight |
| abstractText | Somatic KRAS mutations are highly prevalent in many human cancers. In addition, a distinct spectrum of germline KRAS mutations cause developmental disorders called RASopathies. The mutant proteins encoded by these germline KRAS mutations are less biochemically and functionally activated than the mutant proteins found in cancer. We generated mice harboring conditional KrasLSL-P34R and KrasLSL-T58I "knock in" alleles and characterized the consequences of each mutation in vivo. Embryonic expression of KrasT58I resulted in craniofacial abnormalities reminiscent of RASopathy disorders, and these mice also 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 novel mouse strains are robust models for investigating the consequences of endogenous hyperactive K-Ras signaling 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. |
