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Molecular and Cellular Biology, November 2004, p. 9470-9477, Vol. 24, No. 21
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.21.9470-9477.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

p53 Deficiency Rescues Neuronal Apoptosis but Not Differentiation in DNA Polymerase ß-Deficient Mice

Noriyuki Sugo,^1, Naoko Niimi,¹ Yasuaki Aratani,¹ Keiko Takiguchi-Hayashi,^2* and Hideki Koyama^1*

Kihara Institute for Biological Research and Graduate School of Integrated Science, Yokohama City University, Totsuka-ku, Yokohama,¹ Mitsubishi Kagaku Institute of Life Sciences, Machida-shi, Tokyo, Japan²

Received 27 February 2004/ Returned for modification 29 March 2004/ Accepted 5 August 2004

In mammalian cells, DNA polymerase ß (Polß) functions in base excision repair. We have previously shown that Polß-deficient mice exhibit extensive neuronal cell death (apoptosis) in the developing nervous system and that the mice die immediately after birth. Here, we studied potential roles in the phenotype for p53, which has been implicated in DNA damage sensing, cell cycle arrest, and apoptosis. We generated Polß^–/– p53^–/– double-mutant mice and found that p53 deficiency dramatically rescued neuronal apoptosis associated with Polß deficiency, indicating that p53 mediates the apoptotic process in the nervous system. Importantly, proliferation and early differentiation of neuronal progenitors in Polß^–/– p53^–/– mice appeared normal, but their brains obviously displayed cytoarchitectural abnormalities; moreover, the mice, like Polß^–/– p53^+/+ mice, failed to survive after birth. Thus, we strongly suggest a crucial role for Polß in the differentiation of specific neuronal cell types.

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* Corresponding author. Mailing address for Hideki Koyama: Kihara Institute for Biological Research and Graduate School of Integrated Science, Yokohama City University, 641-12 Maioka-cho, Totsuka-ku, Yokohama 244-0813, Japan. Phone: 81-45-820-1907. Fax: 81-45-820-1901. E-mail: koyama@yokohama-cu.ac.jp. Mailing address for Keiko Takiguchi-Hayashi: Research Laboratory 1 (CNS), Pharmaceuticals Research Unit, Research and Development Division, Mitsubishi Pharma Corp., 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan. Phone: 81-45-963-3413. Fax: 81-45-963-3967. E-mail: Hayashi.Keiko{at}mp.m-pharma.co.jp.

Present address: Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan.

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Molecular and Cellular Biology, November 2004, p. 9470-9477, Vol. 24, No. 21
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.21.9470-9477.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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