Effects of PPARγ and its mew on the development of central nervous system.

中枢神经系统的大部分自我更新依赖于神经干细胞(NSCs)，神经干细胞是一种多能的自我更新的前体细胞。神经干细胞有望用于治疗神经退行性疾病，如帕金森氏病、亨廷顿病和多发性硬化症。然而，控制神经干细胞增殖和分化的详细机制仍不清楚。因此，我们研究了可能影响神经干细胞增殖和分化的各种分子的作用。我们发现PPARγ在胚胎小鼠脑和神经干细胞中高水平表达。相比之下，在成年小鼠的大脑中观察到极低的水平。特异性拮抗剂或慢病毒载体-小干扰RNA抑制PPARγ通路可引起神经干细胞的凋亡。PPARγ基因敲除纯合子小鼠中枢神经系统发育紊乱。这些结果表明PPARγ通路在神经干细胞增殖和中枢神经系统发育中的重要作用。我们还研究了内分泌干扰物(EDs)和非类固醇抗炎药(NSAIDs)对神经干细胞增殖的影响，因为两者都与牙科领域密切相关，可能影响神经干细胞的增殖。双氯芬酸可引起NSCs的凋亡，而其他非甾体抗炎药无此作用。作为内分泌药物之一的壬基酚也可引起NSCs的凋亡。PPARγ、EDs、NSAIDs等多种分子影响神经干细胞的增殖或分化，并可能影响中枢神经系统的发育。

Most self-renewal in the central nervous system is dependent upon neural stem cells (NSCs) that are multi-potent and self-renewing progenitor cells. NSCs are expected to be of utility in the treatment of neurodegenerative disorders, such as Parkinson's disease, Huntington's disease, and multiple sclerosis. However, detailed mechanisms that control proliferation and differentiation of NSCs are still unclear. Therefore, we investigated the effects of various molecules that potentially affect the NSC proliferation and differentiation.We found high-level expression of PPARγ in embryo mouse brain and NSCs. In contrast, extremely low levels were observed in adult mouse brain. Inhibition of PPARγ pathway by specific antagonist or lentiviral vector-siRNA caused apoptosis of NSCs. Homozygous PPARγ-knockout mice showed disorder of the development of central nervous system. Those results indicate the importance of PPARγ pathway on the NSC proliferation and the development of central nervous system.We also investigated the effects of endocrine disruptors (EDs) or non-steroidal anti-inflammatory drugs (NSAIDs) on the proliferation of NSCs, because the both of them are closely related with the field of dentistry potentially affect the NSC proliferation. Diclofenac, but not other NSAIDs, caused apoptosis of NSCs. Nonylphenol, one of the EDs, also caused apoptosis of NSCs. Cell cycle arrest was involved in the mechanisms of both apoptosis.Together with those results, various molecules, such as PPARγ, EDs, and NSAIDs, affect the proliferation or differentiation of NSCs, and may influence the development of central nervous system.