Interruption of cenph causes mitotic failure and embryonic death, and its haploinsufficiency suppresses cancer in zebrafish.
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), that carries the Tol2 transposon element inserted at the kinetochore protein H (cenph) locus. Mutant embryos exhibit discernible cell death as early as 20 hours postfertilization, extensive apoptosis, and upward curly tail during the pharyngula period and deform around 5 days postfertilization. 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 G(2)/M phase. Furthermore, compared with wild type 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.
Zhao
Xinyi
X
Protein Science Laboratory of the Ministry of the Education, College of Life Sciences, Tsinghua University, Beijing 100084, China.
Zhao
Long
L
Tian
Tian
T
Zhang
Yu
Y
Tong
Jingyuan
J
Zheng
Xiaofeng
X
Meng
Anming
A
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002455:Cell Division / Q000235:genetics; D002869:Chromosome Aberrations; D004251:DNA Transposable Elements / Q000235:genetics; D020964:Embryo Loss; D004625:Embryo, Nonmammalian; D047108:Embryonic Development / Q000235:genetics; D005260:Female; D016195:G2 Phase / Q000235:genetics; D056426:Genetic Loci / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D008297:Male; D008769:Methylnitronitrosoguanidine / Q000633:toxicity; D008938:Mitosis / Q000235:genetics*; D016296:Mutagenesis; D009154:Mutation; D009369:Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics*; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
D018797:Cell Cycle Proteins; C552440:Cenph protein, zebrafish; D004251:DNA Transposable Elements; D016159:Tumor Suppressor Protein p53; D029961:Zebrafish Proteins; D008769:Methylnitronitrosoguanidine