9月7日,，神經科學權威雜志The Journal of Neuroscience 在線發(fā)表了上海交通大學醫(yī)學院神經病學研究所，上海生命科學研究院健康科學研究所樂衛(wèi)東教授研究組的最新成果,，揭示了在小鼠中腦發(fā)育過程中,，Pitx3作為關鍵的中間調節(jié)蛋白，介導了GNDF和BDNF對中腦多巴胺能神經元的保護的分子機制,，及其在多巴胺能神經元發(fā)育過程中的功能,。據悉，該項研究成果已得到國家專利授權,。
GDNF 和BDNF是最早發(fā)現的能保護多巴胺能神經元的營養(yǎng)因子,。 中腦多巴胺能神經元表達GDNF受體從而受紋狀體分泌的GDNF的保護,。BDNF也對中腦多巴胺能神經元的發(fā)育有重要作用，條件性敲除后造成了多巴胺能神經元數目的減少,。但目前對于GDNF和BDNF之間的關系及其保護作用的分子機制還不了解,。
樂衛(wèi)東教授指導的博士研究生彭長庚發(fā)現，GDNF 能通過NK-κB信號途徑誘導Pitx3的表達,。Pitx3是一個特異表達于中腦的轉錄因子,，通過激活一系類的多巴胺能神經元內特異分子促進其發(fā)育成熟。GDNF也能促進BDNF在轉錄水平和蛋白水平的表達,，這種促進作用是依賴于Pitx3的,。該研究進一步的研究發(fā)現，BDNF可以在一定程度上挽救Pitx3缺失造成的多巴胺的死亡,。GDNF挽救6-OHDA造成的多巴胺能神經元的死亡也必須依賴于Pitx3,， BDNF的這種保護作用是不依賴于Pitx3的。
該研究首次詳細闡明了GDNF通過Pitx3調節(jié)BDNF進而保護多巴胺能神經元的分子機制,，并揭示了Pitx3在這個過程中的中間調節(jié)者的重要作用,。這對于帕金森病及相關的神經退行性疾病的基因治療提供了重要的分子生物學依據。
該工作得到了國家自然科學基金委及科技部973項目的經費支持,，也得到了德國慕尼黑理工大學發(fā)育與遺傳研究所的協(xié)助,。（生物谷 Bioon.com）
doi:10.1523/JNEUROSCI.0898-11.2011
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Pitx3 Is a Critical Mediator of GDNF-Induced BDNF Expression in Nigrostriatal
Changgeng Peng, Liviu Aron, Rüdiger Klein, Meng Li, Wolfgang Wurst, Nilima Prakash, and Weidong Le,
Pitx3 is a critical homeodomain transcription factor for the proper development and survival of mesodiencephalic dopaminergic (mdDA) neurons in mammals. Several variants of this gene have been associated with human Parkinson's disease (PD), and lack of Pitx3 in mice causes the preferential loss of substantia nigra pars compacta (SNc) mdDA neurons that are most affected in PD. It is currently unclear how Pitx3 activity promotes the survival of SNc mdDA neurons and which factors act upstream and downstream of Pitx3 in this context. Here we show that a transient expression of glial cell line-derived neurotrophic factor (GDNF) in the murine ventral midbrain (VM) induces transcription of Pitx3 via NF-κB-mediated signaling, and that Pitx3 is in turn required for activating the expression of brain-derived neurotrophic factor (BDNF) in a rostrolateral (SNc) mdDA neuron subpopulation during embryogenesis. The loss of BDNF expression correlates with the increased apoptotic cell death of this mdDA neuronal subpopulation in Pitx3−/− mice, whereas treatment of VM cell cultures with BDNF augments the survival of the Pitx3−/− mdDA neurons. Most importantly, only BDNF but not GDNF protects mdDA neurons against 6-hydroxydopamine-induced cell death in the absence of Pitx3. As the feedforward regulation of GDNF, Pitx3, and BDNF expression also persists in the adult rodent brain, our data suggest that the disruption of the regulatory interaction between these three factors contributes to the loss of mdDA neurons in Pitx3−/− mutant mice and perhaps also in human PD
