2008年12月25日美國神經(jīng)科學會刊物《神經(jīng)科學雜志》（The Journal of Neuroscience）在線發(fā)表了中科院神經(jīng)所研究論文，題目是“Lmx1b控制的菱腦峽組織中心在中腦多巴胺神經(jīng)元發(fā)育中起著重要的作用”,。這項研究成果主要是由丁玉強博士實驗室的郭超和仇海燕博士后完成。
由于中腦多巴胺神經(jīng)元在巴金森氏病發(fā)病中的關(guān)鍵作用,，很多研究人員都關(guān)注胚胎發(fā)育時期多巴胺神經(jīng)元的特化、分化和存活的基因調(diào)控途徑,，因為這些研究可能對人工改造胚胎干細胞從而在實驗室制備出用于治療巴金森氏病的多巴胺神經(jīng)元帶來幫助,。
他們先前的研究發(fā)現(xiàn)，一個稱為Lmx1b的轉(zhuǎn)錄因子通過控制菱腦峽組織中心的誘導功能,，從而調(diào)節(jié)中腦和后腦的發(fā)育,。在此基礎(chǔ)上，他們利用條件性基因敲除和轉(zhuǎn)基因技術(shù)研究了Lmx1b在小鼠中腦多巴胺神經(jīng)元發(fā)育中的作用,。他們發(fā)現(xiàn),，胚胎發(fā)育時期常規(guī)Lmx1b敲除小鼠腦內(nèi)中腦多巴胺神經(jīng)元的死亡，是由于菱腦峽組織中心功能缺失引起的,。盡管Lmx1b表達在多巴胺神經(jīng)元內(nèi),，但它對多巴胺神經(jīng)元的分化和存活不是必需的。這一結(jié)果說明,，在多巴胺神經(jīng)發(fā)育中,，神經(jīng)元自身外的因素也起著關(guān)鍵的作用,，拓寬了對多巴胺神經(jīng)元發(fā)育基因調(diào)控方式的認識。（生物谷Bioon.com）
生物谷推薦原始出處：
The Journal of Neuroscience,，28(52):14097-14106,，Chao Guo，Yu-Qiang Ding
Lmx1b-Controlled Isthmic Organizer Is Essential for Development of Midbrain Dopaminergic Neurons
Chao Guo,1 * Hai-Yan Qiu,1,2 * Ming Shi,1 Ying Huang,1 Randy L. Johnson,3 Marcelo Rubinstein,4 Sheng-Di Chen,2 and Yu-Qiang Ding1
1Institute of Neuroscience, Key Laboratory of Neurobiology, Chinese Academy of Sciences, Shanghai 200031, China, 2Department of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China, 3Department of Biochemistry and Molecular Biology, University of Texas, Maryland Anderson Cancer Center, Houston, Texas 77030, and 4Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas and Departmento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires 1428, Argentina
Correspondence should be addressed to Dr. Yu-Qiang Ding, Institute of Neuroscience, Chinese Academy of Sciences, Shanghai 200031, China.
The LIM homeodomain transcription factor Lmx1b has been suggested to be required for the differentiation of midbrain dopaminergic (mDA) neurons. However, whether the loss of mDA neurons in Lmx1b–/– mice is due to its intrinsic role in the mDA lineage or to aconsequence of the malformations caused by the earlier mid/hindbrain patterning defects remains to be clarified. We report here thatLmx1b expression in mDA neurons is dispensable for their differentiation and maintenance, and the loss of mDA neurons in Lmx1b–/–mice is due to the disruption of inductive activity of the isthmic organizer (IsO) in the absence of Lmx1b at the mid/hindbrainboundary (MHB). We found that mDA neurons revealed by tyrosine hydroxylase (TH), Pitx3, Nurr1, and dopamine transporter wereindistinguishable from wild-type controls during embryonic development as well as in adulthood in TH-Cre;Lmx1bflox/– andDatCre/+;Lmx1bflox/– mice, in which Lmx1b was selectively deleted in differentiating mDA neurons. In addition, mDA neurons were recovered in Lmx1b–/– mice, when IsO activity was restored by Wnt1-Lmx1b transgene at MHB. The restored IsO activity was evidenced by apparently normal tectum and cerebellum and recurrence of expression of Fgf8 and Wnt1 at MHB in Wnt1Lmx1b;Lmx1b–/–. Furthermore, when Lmx1b was deleted in the whole brain after the formation of IsO by Nestin-Cre, mDA neurons were normal, whereas serotonergic neurons displayed defective development phenocopying what observed in Lmx1b–/– mice. Thus, our results indicate that the inductive activity of IsO is essential, but Lmx1b expression in mDA neurons is dispensable for their differentiation and maintenance.
