Mutation of DNA primase causes extensive apoptosis of retinal neurons through the activation of DNA damage checkpoint and tumor suppressor p53.
Apoptosis is often observed in developing tissues. However, it remains unclear how the apoptotic pathway is regulated during development. To clarify this issue, we isolated zebrafish mutants that show extensive apoptosis of retinal cells during their development. pinball eye (piy) is one such mutant, in which retinal stem cells proliferate normally but almost all retinal neurons undergo apoptosis during differentiation. We found that a missense mutation occurred in the small subunit of DNA primase (Prim1) in the piy mutant. DNA primase is essential for DNA replication; however, this mutation does not affect cell proliferation but rather induces neuronal apoptosis. RNA synthesis catalyzed by Prim1 is important for the activation of the DNA damage response, which may activate Ataxia telangiectasia mutated (ATM), Checkpoint kinase 2 (Chk2) and the tumor suppressor p53. We found that the apoptosis induced by the prim1 mutation depends on the ATM-Chk2-p53 apoptotic pathway. These data suggest that the surveillance system of genome integrity strongly influences the cell fate decision between differentiation and apoptosis during retinal neurogenesis in zebrafish.
Yamaguchi
Masahiro
M
Developmental Neurobiology Unit, Initial Research Project, Okinawa Institute of Science and Technology Promotion Corporation, 12-2 Suzaki, Uruma-shi, Okinawa 904-2234, Japan.
Fujimori-Tonou
Noriko
N
Yoshimura
Yukihiro
Y
Kishi
Tsutomu
T
Okamoto
Hitoshi
H
Masai
Ichiro
I
D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D064447:Checkpoint Kinase 2; D004249:DNA Damage; D019915:DNA Primase / Q000235:genetics*; D004625:Embryo, Nonmammalian; D004789:Enzyme Activation / Q000235:genetics; D008954:Models, Biological; D020125:Mutation, Missense; D009474:Neurons / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012160:Retina / Q000166:cytology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
D016159:Tumor Suppressor Protein p53; D064447:Checkpoint Kinase 2; D017346:Protein Serine-Threonine Kinases; D019915:DNA Primase