Vesicular monoamine transporter 2 and dopamine transporter are molecular targets of Pitx3 in the ventral midbrain dopamine neurons

• Published in: Journal of neurochemistry 2009-12, Vol.111 (5), p.1202-1212
• Main Authors: Hwang, Dong-Youn, Hong, Sunghoi, Jeong, Joo-Won, Choi, Sangdun, Kim, Hansoo, Kim, Jangwoo, Kim, Kwang-Soo
• Format: Article
• Language: English
• Subjects: Animals; aphakia mice; Biochemistry; Biological and medical sciences; Cell Line, Transformed; Chromatin Immunoprecipitation - methods; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dopamine - metabolism; dopamine neuron; Dopamine Plasma Membrane Transport Proteins - genetics; Dopamine Plasma Membrane Transport Proteins - metabolism; Embryo, Mammalian; Gene expression; Gene Expression Profiling - methods; Gene Expression Regulation, Developmental - drug effects; Gene Expression Regulation, Developmental - genetics; Gene Expression Regulation, Developmental - physiology; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Leukemia Inhibitory Factor - pharmacology; Medical sciences; Mesencephalon - cytology; Mice; Mice, Knockout; Microdissection - methods; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurology; Neurons; Neurons - metabolism; Neurotransmitters; Oligonucleotide Array Sequence Analysis - methods; Parkinson disease; Parkinson’s disease; Pitx3; substantia nigra pars compacta; Transcription Factors - deficiency; Transcription Factors - genetics; Transcription Factors - metabolism; Vesicular Monoamine Transport Proteins - genetics; Vesicular Monoamine Transport Proteins - metabolism
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2009.06404.x

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.