Somatic gain-of-function mutations in the Ras genes are commonly found in the majority of human cancers; whereas, germline gain-of-function mutations in genes of the Ras-Raf-Mek and ERK pathways cause a class of developmental disorders including Noonan, Costello and cardio-facio-cutaneous (CFC) syndromes. It is still unclear how the same activating mutations of the Ras genes can induce both oncogenic transformation, as seen in somatic mutations in cancer patients, as well as developmental abnormalities, as a result of germline mutations, in Noonan, Costello and CFC patients. One possible explanation is that, during development, Ras activates target genes in a limited subtype of cells or tissues, thus curbing the oncogenic activity of mutant Ras and avoiding a lethal phenotype.

In this paper, the zebrafish is used to model Costello syndrome and elucidate oncogenic H-RAS function during development. The authors generated transgenic zebrafish lines expressing oncogenic H-RAS through the germline. These fish show several developmental defects similar to those found in Costello patients. Similar to recent reports in mouse models, no overt activation of the Mek-ERK or PI3K-Akt pathway could be detected in Costello-like fish, suggesting that the molecular mechanism underlying Costello syndrome does not involve activation of these common Ras targets. Among several cellular responses commonly induced by oncogenic Ras, such as proliferation, invasiveness and apoptosis, the authors also observed cellular senescence in adult progenitor cells of the brain and heart – two of the most affected organs in Costello patients.

In this zebrafish model of Costello syndrome, some defects are caused by an oncogene-induced senescence program in adult proliferating cells. This finding encourages further investigation of cellular senescence in Costello patients, who show an age-dependent worsening phenotype that is compatible with premature exhaustion of adult progenitor cells. Additionally, understanding how a developing organism restricts oncogenic signal activation might lead to novel therapeutic strategies in cancer.

2009