title: Peroxisome proliferator-activated receptor gamma-mediated regulation of neural stem cell proliferation and differentiation.
abstract: Peroxisome proliferator-activated receptor gamma (PPARgamma) plays an important role in insulin sensitivity, tissue homeostasis, and regulating cellular functions. We found high-level expression of PPARgamma in embryo mouse brain and neural stem cells (NSCs), in contrast to extremely low levels in adult mouse brain. Here, we show that PPARgamma 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 PPARgamma-deficient mouse brains, PPARgamma-RNA-silenced NSCs, and PPARgamma dominant-negative NSCs were significantly decreased compared with those of wild-type NSCs. Physiological concentrations of PPARgamma 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 PPARgamma 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 PPARgamma by agonists inhibited the differentiation of NSCs into neurons. The inhibition of differentiation was associated with an activation of STAT3. These data indicate that PPARgamma regulates the development of the central nervous system during early embryogenesis via control of NSC proliferation.
authors.affiliation: Department of Pharmacology, Graduate School of Dentistry, Osaka University, 1-8 Yamadaoka, Suita, Osaka 565-0871, Japan. kwada@dent.osaka-u.ac.jp
authors.forename: Koichiro
authors.initials: K
authors.lastname: Wada
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakajima
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Katayama
authors.forename: Chiho
authors.initials: C
authors.lastname: Kudo
authors.forename: Atsuhito
authors.initials: A
authors.lastname: Shibuya
authors.forename: Naoto
authors.initials: N
authors.lastname: Kubota
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Terauchi
authors.forename: Masashi
authors.initials: M
authors.lastname: Tachibana
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyoshi
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Kamisaki
authors.forename: Tadanori
authors.initials: T
authors.lastname: Mayumi
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
authors.forename: Richard S
authors.initials: RS
authors.lastname: Blumberg
mesh_terms: D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D049109:Cell Proliferation; D004815:Epidermal Growth Factor / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009474:Neurons / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism*
chemical_list: D047495:PPAR gamma; D004815:Epidermal Growth Factor