生物谷报道：研究人员找到了一个新的microRNA, miR-133b,并发现它在中脑多巴胺能神经元的成熟、功能、和存活上起作用。帕金森症患者的中脑中，这些miR-133b细胞缺乏。研究结果发表在最新一期的《科学》杂志上。
帕金森症是一种由大脑的多巴胺能神经元产生的多巴胺形状和行为有问题引起的运动紊乱。Jongpil Kim和同事还发现，miR-133b与Pitx3形成一个反馈圈，Pitx3是中脑多巴胺能神经元的一个关键的转录调节因子。在一片相关的研究评述中， Sébastien S. Hébert和Bart de Strooper 写道，microRNA网络与人类的疾病有关，包括心脏病、癌症、阿尔茨海默氏病、Tourette综合征，现在被发现也与帕金森症有关。他们提议，这个发现以及在神经退化疾病领域的其他发现也许能帮助阐明microRNA 涉及这类疾病的程度，他们指出，“microRNA做为治疗疾病的靶标仍是一个极具挑战的课题”。
Fig. 1. Dicer is essential for the midbrain DN phenotype. (A) Floxed Dicer conditional knockout ES cultures (flx/flx) were differentiated by the EB method, transduced with Cre or control green fluorescent protein (GFP) lentivirus, and analyzed by immunostaining with antibodies specific for TH (red), TujI (green), and GABA (blue). Cultures transduced with a lentiviral Cre vector (vCre) but not control GFP lentivirus (vGFP) were essentially devoid of TH+ neurons, whereas TujI+ and GABA+ cells were reduced by approximately 40 to 60%. (n = 3 independent samples per group). Scale bar, 100 µm. Data represent mean ± SEM; analysis of variance (ANOVA) test, *P < 0.05. (B) The Dicer deletion phenotype, as in (A), can be "rescued" by transfection of midbrain-derived small RNAs (<200 base pairs) but not large RNAs (>200 base pairs). Two independent experiments of three sets each were performed, with 10 visual fields per set; data represent mean ± SEM; ANOVA test, **P < 0.01. (C) Immunostaining of brain sections from 8-week-old DATCRE/+:Dicer flox/flox mice for TH demonstrates loss of 90% of midbrain DNs in the substantia nigra (SN) and ventral tegmental area (VTA) and their axonal projections to the striatum relative to control littermates (DATCRE/+:Dicer flox/+)(n = 3 for each genotype). Scale bars, 200 µm. (D) Locomotor activity of DATCRE/+:Dicerflox/flox mice in the open field. The total distance traveled was significantly decreased in DATCRE/+:Dicerflox/flox mice (n = 4 for each genotype). Data represent mean ± SEM; Student's t test, *P < 0.05,**P < 0.01. [View Larger Version of this Image (197K JPEG file)]
原文出处：
Science 31 August 2007 Vol 317, Issue 5842
A MicroRNA Feedback Circuit in Midbrain Dopamine Neurons
Jongpil Kim, Keiichi Inoue, Jennifer Ishii, William B. Vanti, Sergey V. Voronov, Elizabeth Murchison, Gregory Hannon, and Asa Abeliovich
Science 31 August 2007: 1220-1224.
MicroRNAs are required for the maturation and function of midbrain dopamine neurons, and loss of a particular miRNA may underlie Parkinson抯 disease.
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作者简介：
Asa Abeliovich, M.D., Ph.D.
Assistant Professor of Pathology and Neurology
Research Summary
Molecular mechanisms of neurodegeneration and the life cycle of dopamine neurons.
We are studying the molecular bases of midbrain dopamine neuron development, function and survival. Midbrain dopamine neurons are thought to play key roles in learned and addictive behaviors, and degeneration of these neurons underlies Parkinson's disease.
A focus of the lab is to understand the mechanisms by which mutations in Parkinson’s disease-related genes, such as a-synuclein and parkin, lead to midbrain dopamine neuron dysfunction and eventual demise. We are also particularly interested in the normal cellular roles of these genes. We use a combination of molecular biological, cellular, and mouse genetic approaches to this end.
In a second project, we are characterizing molecules that play a important roles in the specification and late development of dopamine neurons using an in vitro culture system. Embryonic stem cells have been shown to give rise to dopamine neurons in response to a set of extrinsic cues such as sonic hedgehog and FGF8. Furthermore, a few intrinsic cellular factors, such as nurr1, have been implicated in the generation of dopamine neurons. We are using molecular biological tools to investigate the mechanism by which such intrinsic signals determine midbrain dopamine neuron fate.
Selected Publications
1. Abeliovich, A., Schmitz, Y., Farinas, I., Choi-Lundberg, D., Ho, W.-H., Verdugo, J. M. G., Armanini, M., Ryan, A., Hynes, M., Phillips, H., Sulzer, D., and Rosenthal, A. (1999). Mice lacking a-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25, 239-252.
2. Staropoli, J. F., McDermott, C., Martinat, C., Schulman, B., Demireva, E, and Abeliovich, A. (2003). Parkin is a Component of an SCF-like Ubiquitin Ligase Complex and Protects Postmitotic Neurons from Kainate Excitotoxicity. Neuron 37: 735-749.
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Honors and Awards
1988 Medical Scientist Training Program Predoctoral Fellowship, Harvard Medical School
2001 Culpeper Scholar, Rockefeller Brothers Foundation
2001 Beeson Scholar, American Federation for Aging Research
2001 Mathissen Foundation Award, Columbia University
Keywords
Parkinson's disease, gene expression, gene mutation, genetic disorder, neurogenetics, neuropathology, dopamine, neural degeneration, neuron, protein structure function, ubiquitin, gene targeting, immunocytochemistry, laboratory mouse.
相关基因：
MIRN133B
Official Symbol MIRN133B and Name: microRNA 133b [Homo sapiens]
Other Aliases: MIR133B, mir-133b
Chromosome: 6
MIM: 610946
GeneID: 442890
