2008年12月25日美国神经科学会刊物《神经科学杂志》（The Journal of Neuroscience）在线发表了中科院神经所研究论文，题目是“Lmx1b控制的菱脑峡组织中心在中脑多巴胺神经元发育中起着重要的作用”。这项研究成果主要是由丁玉强博士实验室的郭超和仇海燕博士后完成。

    由于中脑多巴胺神经元在巴金森氏病发病中的关键作用，很多研究人员都关注胚胎发育时期多巴胺神经元的特化、分化和存活的基因调控途径，因为这些研究可能对人工改造胚胎干细胞从而在实验室制备出用于治疗巴金森氏病的多巴胺神经元带来帮助。

    他们先前的研究发现，一个称为Lmx1b的转录因子通过控制菱脑峡组织中心的诱导功能，从而调节中脑和后脑的发育。在此基础上，他们利用条件性基因敲除和转基因技术研究了Lmx1b在小鼠中脑多巴胺神经元发育中的作用。他们发现，胚胎发育时期常规Lmx1b敲除小鼠脑内中脑多巴胺神经元的死亡，是由于菱脑峡组织中心功能缺失引起的。尽管Lmx1b表达在多巴胺神经元内，但它对多巴胺神经元的分化和存活不是必需的。这一结果说明，在多巴胺神经发育中，神经元自身外的因素也起着关键的作用，拓宽了对多巴胺神经元发育基因调控方式的认识。

推荐原始出处：

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.