中腦的多巴胺神經元（dopaminergic neuron, mDA neuron）退化是帕金森氏症的病理性特徵。目前已經知道有許多的發育相關的轉錄因子以及神經滋養因子會參與中腦多巴胺神經元的分化以及存活。在我們實驗室先前的研究中發現不管在體內或體外的實驗，纖維母細胞生長因子9 (FGF9) 對於多巴胺神經元的存活扮演重要的角色。因此，我們試圖探討纖維母細胞生長因子9在人類 LUHMES 細胞的多巴胺神經元分化中所扮演的角色。首先，我們建立了在體外培養多巴胺神經細胞分化的模式，使用cAMP以及glia cell line-derived neurotrophic factor (GDNF)， LUHMES細胞可以分化成成熟的多巴胺神經細胞，並且可以使用多巴胺神經元的標誌物，tyrosine hydroxylase (TH)、dopamine receptor 2 (D2R) 以及dopamine transporter (DAT)，以及轉錄因子Lmx1b和Nurr1的表現增加，鑑定成熟的多巴胺神經元。然而，在缺少cAMP和GDNF的情況下，多巴胺神經元標誌物不能大量表達，所以LUHMES細胞會分化成非多巴胺的神經細胞。我們發現在缺少cAMP和GDNF的情況下，與分化時間 (D2-D6) 有相關的 FGF9 mRNA表現的增加被抑制。此外在使用cAMP和GDNF共同培養的LUHMES細胞中，細胞的FGF9水平和蛋白質表現以及 FGF9 promoter驅動的DsRed螢光皆在分化第二天顯著且短暫地增加。我們更進一步的使用 FGFR 的抑制劑 PD173074 或 FGF9 的抗體，阻斷 FGF9 到 FGFR 的訊息傳遞，結果顯示TH、D2R和DAT 的螢光表現顯著的下降，抑制多巴神經元的分化。另一方面，我們在缺乏 cAMP 以及 GDNF 的情況下，給予 FGF9，會促進 TH以及D2R 的表現。這樣的結果表示， FGF9 在LUHMES細胞多巴胺神經元分化的調控中起著重要的作用。

Loss of ventral midbrain dopaminergic (mDA) neurons is a characteristic feature of Parkinson’s disease (PD). Several developmental transcriptional factors and trophic factors are required for the mDA neuron differentiation and survival. Our previous studies demonstrated that fibroblast growth factor 9 (FGF9) is a survival factor for mDA neuron in vivo and in vitro. In the present study, we attempt to investigate the role of FGF9 on the mDA neuron differentiation in Lund human mesencephalic (LUHMES) cells. First, we established an in vitro mDA neuron differentiation model that in the culture medium containing cAMP and glia cell line-derived neurotrophic factor (GDNF), LUHMES cells can be fully differentiated into mature DA neurons as identified by the upregulation of selective DA neuron markers, tyrosine hydroxylase (TH) and dopamine receptor 2 (D2R) and dopamine transporter (DAT), and transcription factor of Lmx1b and Nurr1. However, in the absence of cAMP and GDNF, LUHMES cells were differentiated into non-DA neuron which did not express high levels of selective DA markers. We found that in the absence of cAMP and GDNF, the increase of FGF9 mRNA expression associated with differentiation days (D2-D6) was abolished. Moreover, the cellular FGF9 level and protein expression, as well as FGF9 promoter-drived DsRed fluorescence was significantly but transiently increased at D2 in LUHMES cells cultured with cAMP and GDNF. The blockage of FGF9-FGFR signaling pathway by FGFR inhibitor PD173074 or anti-FGF9 neutralized antibody inhibited DA neuron differentiation as indicated by a significant decrease in TH and DAT and D2R immunofluorescence. On the other hand, in the absence cAMP and GDNF, the treatment of recombinant FGF9 protein dramtically enhanced TH and D2R expression. Accordingly, our results demonstrated that FGF9 plays an essential role in the control of DA neuron differentiation in human LUHMES cells.

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