brca2-mutant zebrafish exhibit context- and tissue-dependent alterations in cell phenotypes and response to injury

Abstract

Cancer cells frequently co-opt molecular programs that are normally activated in specific contexts, such as embryonic development and the response to injury. Determining the impact of cancer-associated mutations on cellular phenotypes within these discrete contexts can provide new insight into how such mutations lead to dysregulated cell behaviors and subsequent cancer onset. Here we assess the impact of heritable BRCA2 mutation on embryonic development and the injury response using a zebrafish model (Danio rerio). Unlike most mouse models for BRCA2 mutation, brca2-mutant zebrafish are fully viable and thus provide a unique tool for assessing both embryonic and adult phenotypes. We find that maternally provided brca2 is critical for normal oocyte development and embryonic survival in zebrafish, suggesting that embryonic lethality associated with BRCA2 mutation is likely to reflect defects in both meiotic and embryonic developmental programs. On the other hand, we find that adult brca2-mutant zebrafish exhibit aberrant proliferation of several cell types under basal conditions and in response to injury in tissues at high risk for cancer development. These divergent effects exemplify the often-paradoxical outcomes that occur in embryos (embryonic lethality) versus adult animals (cancer predisposition) with mutations in cancer susceptibility genes such as BRCA2. The altered cell behaviors identified in brca2-mutant embryonic and adult tissues, particularly in adult tissues at high risk for cancer, indicate that the effects of BRCA2 mutation on cellular phenotypes are both context- and tissue-dependent.

The molecular evolution of cancer associated genes in mammals

“…Casp8, CD274 and B2M’s involvement in immunity 84 , 85 , was likely driving positive selection in these genes. Interestingly, BRCA2, a key gene involved with DNA repair as well as with embryogenesis 86 showed signatures of episodic selection in 8 out of the 9 taxonomic groups studied here. A potential explanation for this conundrum (as high conservancy of this gene could be expected due to its critical role in cellular functions) could be its large size (10,254 bp nucleotides) and involvement of its different domains with multiple functions 87 .…”