Peroxisome Proliferator-activated Receptor γ-mediated Regulation of Neural Stem Cell Proliferation and Differentiation*
Peroxisome Proliferator-activated Receptor γ-mediated Regulation of Neural Stem Cell Proliferation and Differentiation*
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DOI：
10.1074/jbc.m513786200
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发表时间：
2006-05
影响因子：
4.8
通讯作者：
K. Wada;A. Nakajima;K. Katayama;Chiho Kudo;A. Shibuya;N. Kubota;Y. Terauchi;M. Tachibana;H. Miy
中科院分区：
文献类型：
--
作者：
K. Wada;A. Nakajima;K. Katayama;Chiho Kudo;A. Shibuya;N. Kubota;Y. Terauchi;M. Tachibana;H. Miy
过氧化物酶体增殖物激活受体γ（Peroxisome proliferator-activated receptor γ，PPARγ）在胰岛素敏感性、组织稳态和细胞功能调节中起重要作用。我们在胚胎小鼠脑和神经干细胞（NSCs）中发现了高水平的PPARγ表达，而在成年小鼠脑中的表达水平极低。在此，我们发现，PPARγ通过上调表皮生长因子受体和激活ERK通路介导小鼠神经干细胞的增殖和分化。与野生型NSCs相比，从杂合型PPARγ缺陷小鼠脑制备的NSCs、PPARγ-RNA沉默的NSCs和PPARγ显性阴性的NSCs的细胞生长速率显著降低。生理浓度的PPARγ激动剂罗格列酮和吡格列酮刺激NSC生长，而拮抗剂通过激活caspase级联以浓度依赖性方式引起细胞死亡。通过磷酸化和上调表皮生长因子受体和细胞周期蛋白B蛋白水平，通过PPARγ刺激细胞生长与ERK通路的快速激活相关。与此相反，通过激动剂激活PPARγ抑制NSCs向神经元的分化。分化的抑制与STAT 3的激活有关。这些数据表明，在早期胚胎发育过程中，PPARγ通过控制NSC增殖来调节中枢神经系统的发育。
Peroxisome proliferator-activated receptor γ (PPARγ) plays an important role in insulin sensitivity, tissue homeostasis, and regulating cellular functions. We found high-level expression of PPARγ in embryo mouse brain and neural stem cells (NSCs), in contrast to extremely low levels in adult mouse brain. Here, we show that PPARγ 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 PPARγ-deficient mouse brains, PPARγ-RNA-silenced NSCs, and PPARγ dominant-negative NSCs were significantly decreased compared with those of wild-type NSCs. Physiological concentrations of PPARγ 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 PPARγ 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 PPARγ by agonists inhibited the differentiation of NSCs into neurons. The inhibition of differentiation was associated with an activation of STAT3. These data indicate that PPARγ regulates the development of the central nervous system during early embryogenesis via control of NSC proliferation.