| Popis: |
Pleiotropy caused by single-gene mutations is common and poorly understood. A zebrafish null mutant of DNA polymerase α subunit B,huli hutu(hht), evolves a complex pleiotropy associated with DNA damage and S phase arrest across multiple organ systems over 5-7 days, including nuclear atypia, a common cellular feature in human cancers and pre-cancers, in gastrointestinal organs, and nuclear fragmentation in the eye and brain. The pleiotropic pattern ofhhtphenotypes is explained by progressive loss of wild-type maternalpola2function in homozygous mutant embryos whosepola2mRNA becomes undetectable by 24 hours post-fertilization (hpf). Inhibition of DNA synthesis by aphidicolin or hydroxyurea in wild-type embryos from 24 hpf phenocopied the pleiotropic pattern ofhht. These results are consistent with a model in which time-sensitive, reduced capacity for DNA synthesis results in cell death in fast-replicating cells, and nuclear atypia in tissues with fewer and larger cells. |
