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J. Biol. Chem., Vol. 281, Issue 18, 12673-12681, May 5, 2006
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Peroxisome Proliferator-activated Receptor 
-mediated Regulation of Neural Stem Cell Proliferation and Differentiation*
1
¶2
From the
Department of Pharmacology, Graduate School of Dentistry, Osaka University, 1-8 Yamadaoka, Suita, Osaka 565-0871, Japan, the Gastroenterology Division, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, ¶The Third Department of Internal Medicine, Yokohama City University School of Medicine, 3-9 Fuku-ura, Yokohama 236-0004, Japan, the ||Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan, the **Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan, and the Subteam for Manipulation of Cell Fate, BioResource Center, RIKEN, Tsukuba Institute, Ibaraki, 305-0074, Japan
Peroxisome proliferator-activated receptor 
(PPAR) plays an important role in insulin sensitivity, tissue homeostasis, and regulating cellular functions. We found high-level expression of PPAR in embryo mouse brain and neural stem cells (NSCs), in contrast to extremely low levels in adult mouse brain. Here, we show that PPAR mediates the proliferation and differentiation of murine NSCs via up-regulation of the epidermal growth factor receptor and activation of the ERK pathway. Cell growth rates of NSCs prepared from heterozygous PPAR-deficient mouse brains, PPAR-RNA-silenced NSCs, and PPAR dominant-negative NSCs were significantly decreased compared with those of wild-type NSCs. Physiological concentrations of PPAR agonists, rosiglitazone and pioglitazone, stimulated NSC growth, whereas antagonists caused cell death in a concentration-dependent manner via activation of the caspase cascade. The stimulation of cell growth by PPAR was associated with a rapid activation of the ERK pathway by phosphorylation and up-regulation of epidermal growth factor receptor and cyclin B protein levels. In contrast, activation of PPAR by agonists inhibited the differentiation of NSCs into neurons. The inhibition of differentiation was associated with an activation of STAT3. These data indicate that PPAR regulates the development of the central nervous system during early embryogenesis via control of NSC proliferation.
Received for publication, December 27, 2005 , and in revised form, February 27, 2006.
* This work was supported in part by Grant Tokuteiryouiki C13204072 (to A. N.) from the Ministry of Education, Culture, Sports, Science and Technology, Japan Society for the Promotion of Science Grant 15590227 (to K. W.), and a grant from COE frontier Bioscience in Osaka University (to K. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
2 Supported by National Institutes of Health Grants DK44319, DK51362, and DK53056 and the Harvard Digestive Disease Center.
1 To whom correspondence should be addressed. Tel.: 81-6-6879-2913; Fax: 81-6-6879-2914; E-mail: kwada{at}dent.osaka-u.ac.jp.
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