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帕金森病 Parkinson's disease
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webmaster:驱动和维持多巴胺能神经元末端分化的充要条件(有关干细胞)  IP:119.134.20.57  日期:2009-4-18 [回复1楼]

  驱动和维持多巴胺能神经元末端分化的充要条件(有关干细胞)
  
  产生作为神经传输物质多巴胺的神经元控制一系列脑功能,包括运动控制、认知、动机和快感。前体细胞在这些功能所涉及的数量巨大的发育线路中是怎样选择其中一个线路——即选择多巴胺能这一命运的一直不清楚。
  
  现在,Nuria Flames 和Oliver Hobert报告说,调控蛋白AST-1是线虫C. elegans体内驱动和维持多巴胺能神经元的末端分化的必要和充分条件。由于该蛋白及其末端分化功能在小鼠身上被惊人地保留了下来,所以这些结果对于多巴胺相关疾病如帕金森氏症的干细胞替换疗法有直接意义。
  
  原文:
  
  Nature 458, 885-889 (16 April 2009) | doi:10.1038/nature07929
  
  Gene regulatory logic of dopamine neuron differentiation
  
  Nuria Flames1 & Oliver Hobert1
  
  Howard Hughes Medical Institute, Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, New York 10032, USA
  
  Dopamine signalling regulates a variety of complex behaviours, and defects in dopamine neuron function or survival result in severe human pathologies, such as Parkinson’s disease1. The common denominator of all dopamine neurons is the expression of dopamine pathway genes, which code for a set of phylogenetically conserved proteins involved in dopamine synthesis and transport. Gene regulatory mechanisms that result in the direct activation of dopamine pathway genes and thereby ultimately determine the identity of dopamine neurons are poorly understood in all systems studied so far2. Here we show that a simple cis-regulatory element, the dopamine (DA) motif, controls the expression of all dopamine pathway genes in all dopaminergic cell types in Caenorhabditis elegans. The DA motif is activated by the ETS transcription factor AST-1. Loss of ast-1 results in the failure of all distinct dopaminergic neuronal subtypes to terminally differentiate. Ectopic expression of ast-1 is sufficient to activate the dopamine pathway in some cellular contexts. Vertebrate dopamine pathway genes also contain phylogenetically conserved DA motifs that can be activated by the mouse ETS transcription factor Etv1 (also known as ER81), and a specific class of dopamine neurons fails to differentiate in mice lacking Etv1. Moreover, ectopic Etv1 expression induces dopaminergic fate marker expression in neuronal primary cultures. Mouse Etv1 can also functionally substitute for ast-1 in C. elegans. Our studies reveal a simple and apparently conserved regulatory logic of dopamine neuron terminal differentiation and may provide new entry points into the diagnosis or therapy of conditions in which dopamine neurons are defective.
   

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