Vesicular monoamine transporter 2 and dopamine transporter are molecular targets of Pitx3 in the ventral midbrain dopamine neurons.
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.
Molecular Neurobiology Laboratory, McLean Hospital and Harvard Medical School, Belmont, MA, USA.
Dong-Youn
DY
Hwang
Sunghoi
S
Hong
Joo-Won
JW
Jeong
Sangdun
S
Choi
Hansoo
H
Kim
Jangwoo
J
Kim
Kwang-Soo
KS
Kim
D000818:Animals; D002461:Cell Line, Transformed; D047369:Chromatin Immunoprecipitation / Q000379:methods; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian; D020869:Gene Expression Profiling / Q000379:methods; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053605:Leukemia Inhibitory Factor / Q000494:pharmacology; D008636:Mesencephalon / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D042282:Microdissection / Q000379:methods; D009474:Neurons / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050493:Vesicular Monoamine Transport Proteins / Q000235:genetics / Q000378:metabolism*
D050483:Dopamine Plasma Membrane Transport Proteins; D018398:Homeodomain Proteins; D053605:Leukemia Inhibitory Factor; D014157:Transcription Factors; D050493:Vesicular Monoamine Transport Proteins; C433629:homeobox protein PITX3; D004298:Dopamine