N-methyl-N-nitrosourea-induced retinal degeneration in mice is independent of the p53 gene.
OBJECTIVE
A single systemic administration of N-methyl-N-nitrosourea (MNU) causes retinal degeneration involving photoreceptor cell loss within 7 days. MNU-induced photoreceptor cell loss is due to apoptosis and is a reliable animal model for human retinitis pigmentosa. The purpose of this study was to determine if p53 contributes to the development of MNU-induced retinal degeneration in mice.


METHODS
Eight-week-old p53(-/-), p53(+/-), and p53(+/+) mice received an intraperitoneal injection of 60 mg/kg bodyweight of MNU. Age-matched p53(+/+) mice received the vehicle only (physiologic saline containing 0.05% acetic acid). Mice were sacrificed and necropsied 7 days after the treatment. Both eyes were examined histologically and morphometrically to determine retinal thickness, photoreceptor cell ratio, and retinal damage ratio.


RESULTS
No mice died during the experiment, but the p53 null mice treated with MNU had a statistically significant weight loss compared to the other groups. Histologically, all MNU-treated mice, regardless of p53 gene status, experienced retinal degeneration characterized by photoreceptor cell loss (the disappearance of the outer nuclear layer and photoreceptor layer) in both the central and peripheral retina. All MNU-treated mice had significantly decreased retinal thickness and photoreceptor cell ratios at the central and peripheral retina and an increased retinal damage ratio compared to the vehicle-treated control. The retinal changes caused by MNU in p53(+/+), p53(+/-), and p53(-/-) mice were not significantly different and hence were related to a p53-independent apoptotic mechanism.


CONCLUSIONS
Because the absence of p53 did not prevent photoreceptor cell loss, we conclude that p53 is not essential for MNU-mediated photoreceptor cell degeneration.
Yoshizawa
Katsuhiko
K
Second Department of Pathology, Kansai Medical University, Moriguchi, Osaka, Japan. yoshizak@takii.kmu.ac.jp
Kuwata
Maki
M
Kawanaka
Ayako
A
Uehara
Norihisa
N
Yuri
Takashi
T
Tsubura
Airo
A
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002452:Cell Count; D005260:Female; D008770:Methylnitrosourea / Q000008:administration & dosage / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012160:Retina / Q000187:drug effects / Q000473:pathology; D012162:Retinal Degeneration / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics
D016159:Tumor Suppressor Protein p53; D008770:Methylnitrosourea