Zhao, X., Zhao, L., Tian, T., Zhang, Y., Tong, J., Zheng, X., and Meng, A. (2010) Interruption of cenph causes mitotic failure and embryonic death and its haploinsufficiency suppresses cancer in zebrafish. The Journal of biological chemistry. 285(36):27924-27934.
Kinetochore proteins associate with centromeric DNA and spindle microtubules and play essential roles in chromosome segregation during mitosis. In this study, we uncovered a zebrafish mutant, stagnant and curly (stac), which carries the Tol2-transposon element inserted at the kinetochore protein H (cenph) locus. Mutant embryos exhibit discernible cell death as early as 20 hpf, extensive apoptosis and upward curly tail during pharyngula period, and deform around 5 dpf. The stac mutant phenotype can be rescued by cenph mRNA overexpression, and mimicked by cenph knockdown with antisense morpholinos, suggesting the responsibility of cenph deficiency for stac mutants. We demonstrate that the intrinsic apoptosis pathway is hyperactivated in stac mutants and that p53 knockdown partially blocks excess apoptosis in stac mutants. Mitotic cells in stac mutants show chromosome missegregation and are usually arrested in G2/M phase. Furthermore, compared to wildtype siblings, heterozygous stac fish develop invasive tumors at a dramatically reduced rate, suggesting a reduced cancer risk. Taken together, our findings uncover an essential role of cenph in mitosis and embryonic development and its association with tumor development.