Journal
JOURNAL OF NEUROCHEMISTRY
Volume 111, Issue 5, Pages 1202-1212Publisher
WILEY
DOI: 10.1111/j.1471-4159.2009.06404.x
Keywords
aphakia mice; dopamine neuron; Parkinson's disease; Pitx3; substantia nigra pars compacta
Categories
Funding
- NIH [MH48866, DC006501]
- Michael J Fox Foundation for Parkinson's Research
- Brain and Stem Cell Research Centers [SC5130, SC5170]
- Ministry of Education, Science and Technology
- Republic of Korea
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Midbrain dopamine (mDA) neurons play critical roles in the regulation of voluntary movement and their dysfunction is associated with Parkinson's disease. Pitx3 has been implicated in the proper development of mDA neurons in the substantia nigra pars compacta, which are selectively lost in Parkinson's disease. However, the basic mechanisms underlying its role in mDA neuron development and/or survival are poorly understood. Toward this goal, we sought to identify downstream target genes of Pitx3 by comparing gene expression profiles in mDA neurons of wild-type and Pitx3-deficient aphakia mice. This global gene expression analysis revealed many potential target genes of Pitx3; in particular, the expression of vesicular monoamine transporter 2 and dopamine transporter, responsible for dopamine storage and reuptake, respectively, is greatly reduced in mDA neurons by Pitx3 ablation. In addition, gain-of-function analyses and chromatin immunoprecipitation strongly indicate that Pitx3 may directly activate transcription of vesicular monoamine transporter 2 and dopamine transporter genes, critically contributing to neurotransmission and/or survival of mDA neurons. As the two genes have been known to be regulated by Nurr1, another key dopaminergic transcription factor, we propose that Pitx3 and Nurr1 may coordinately regulate mDA specification and survival, at least in part, through a merging and overlapping downstream pathway.
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