9月7日,，神經(jīng)科學(xué)權(quán)威雜志The Journal of Neuroscience 在線發(fā)表了上海交通大學(xué)醫(yī)學(xué)院神經(jīng)病學(xué)研究所,，上海生命科學(xué)研究院健康科學(xué)研究所樂(lè)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(guò)程中，Pitx3作為關(guān)鍵的中間調(diào)節(jié)蛋白,，介導(dǎo)了GNDF和BDNF對(duì)中腦多巴胺能神經(jīng)元的保護(hù)的分子機(jī)制,，及其在多巴胺能神經(jīng)元發(fā)育過(guò)程中的功能。據(jù)悉,，該項(xiàng)研究成果已得到國(guó)家專利授權(quán),。
GDNF 和BDNF是最早發(fā)現(xiàn)的能保護(hù)多巴胺能神經(jīng)元的營(yíng)養(yǎng)因子。 中腦多巴胺能神經(jīng)元表達(dá)GDNF受體從而受紋狀體分泌的GDNF的保護(hù),。BDNF也對(duì)中腦多巴胺能神經(jīng)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(jīng)元數(shù)目的減少。但目前對(duì)于GDNF和BDNF之間的關(guān)系及其保護(hù)作用的分子機(jī)制還不了解,。
樂(lè)衛(wèi)東教授指導(dǎo)的博士研究生彭長(zhǎng)庚發(fā)現(xiàn),，GDNF 能通過(guò)NK-κB信號(hào)途徑誘導(dǎo)Pitx3的表達(dá)。Pitx3是一個(gè)特異表達(dá)于中腦的轉(zhuǎn)錄因子,，通過(guò)激活一系類的多巴胺能神經(jīng)元內(nèi)特異分子促進(jìn)其發(fā)育成熟,。GDNF也能促進(jìn)BDNF在轉(zhuǎn)錄水平和蛋白水平的表達(dá)，這種促進(jìn)作用是依賴于Pitx3的,。該研究進(jìn)一步的研究發(fā)現(xiàn)，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(jīng)元的死亡也必須依賴于Pitx3,， BDNF的這種保護(hù)作用是不依賴于Pitx3的。
該研究首次詳細(xì)闡明了GDNF通過(guò)Pitx3調(diào)節(jié)BDNF進(jìn)而保護(hù)多巴胺能神經(jīng)元的分子機(jī)制,，并揭示了Pitx3在這個(gè)過(guò)程中的中間調(diào)節(jié)者的重要作用,。這對(duì)于帕金森病及相關(guān)的神經(jīng)退行性疾病的基因治療提供了重要的分子生物學(xué)依據(jù)。
該工作得到了國(guó)家自然科學(xué)基金委及科技部973項(xiàng)目的經(jīng)費(fèi)支持,，也得到了德國(guó)慕尼黑理工大學(xué)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
PMC:
PMID:
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
