アクティブボード・２００７年１０月
　　　　　・・・・・２００７年１０月　１日更新・・・・・

研究発表を行った学会；
・第１回グローバルCOEサマーリトリートセミナー、2007年 9月28~29日(熊本)

タイトル；Inhibition of astrocyte differentiation by cyclin D1.
発表者；　備前　典久　氏
　　　（熊本大学　発生医学研究センター　転写制御分野）
Abstract；
We have previously shown that neural stem cells (NSCs) are differentiated into astrocytes in synergy by LIF (leukemia inhibitory factor) and BMP2 (bone morphogenic protein-2). We demonstrated that two transcription factors STAT3 (signal transducers and activators of transcription-3) and Smad1, which are activated by LIF and BMP2, form a complex with a transcriptional coactivator p300, which explains the synergistic function of LIF and BMP2 (Nakashima, K et al. Science 1999). However, this model does not fully explain the molecular basis for the link between induction of differentiation and inhibition of cell cycle progression during astrogliogenesis. Besides induction of astrocyte differentiation, LIF is known to induce cyclin D1 expression and promote cell proliferation. Recent report showed that cyclin D1 repressed LIF-induced transactivation of STAT3, providing a negative feedback regulation of STAT3 activity (Bienvenu F, et al. J Biol Chem 2001). Since BMP2 represses cell proliferation, we hypothesized that BMP2 signaling reduced cyclin D1 expression to derepress transactivation of STAT3 and, thus, facilitated astrogliogenesis. To invistigate this possibility, neuroepithelial cells from embryonic day 14.5 mouse telencephalon were cultured with FGF2 (fibroblast growth factor-2) for 4 days to enrich NSCs, and then treated with or without LIF and BMP2 for 12 hours. LIF stimulation by itself increased the number of cyclin D1 positive cells, whereas simultaneous stimulation with LIF plus BMP2 decreased it by less than half. Interestingly, GFAP (glial fibrillary acidic protein, an astrocyte marker)-expressing cells did not express cyclin D1. Forced expression of cyclin D1 in NSCs cultured with LIF and BMP2 decresed the number of GFAP expressing cells down to about 20% of the control. Forced expression of cyclin D1 also decreased GFAP promoter activity by about 70% in the presence of LIF and BMP2. Since cyclin D1 is highly expressed in proliferating NSCs, we propose here in this study that cyclin D1 plays an important role in the maintenance of the undifferentiated state of NSCs by preventing astrogliogenesis.