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

Abstract

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.

Functional Roles of Nurr1, Pitx3, and Lmx1a in Neurogenesis and Phenotype Specification of Dopamine Neurons During In Vitro Differentiation of Embryonic Stem Cells

“…Based on our recent identification of the proneural gene Ngn2 as a potential target of Pitx3 [44], we hypothesized that differential regulation of Ngn2 by Pitx3, Nurr1, and/or Lmx1a may underlie the above distinct functional roles by these transcription factors. To test this, we examined Ngn2 mRNA expression by qPCR analysis in differentiated neuronal cells of Nurr1-, Pitx3-, and Lmx1a-transduced cells.…”

Meta-analysis of association between PITX3 gene polymorphism and Parkinson's disease

“…Clinically, the first motor symptoms of PD are observable when 60-80% of the DAergic neurons are lost [6]. PITX3 (paired-like homeodomain transcription factor 3) belonging to a pituitary homeobox subfamily, and being a homeodomaincontaining transcription factor [7], is essential to the differentiation and maintenance of DA neurons in midbrain during development [8,9]. From this, we can hypothesize that a polymorphism in the PITX3 region can lead to the loss of DAergic neurons resulting in PD.…”

Dopaminergic Neurons Derived from Human Embryonic Stem Cell Derived Neural Progenitors: Biological Relevance and Application

“…However, this is only required during early development and does not account for the continued deficits seen in aphakia mice (Jacobs et al, 2007). A possible role for PITX3 in continued deficits is in its control of VMAT2 and DAT expression (Hwang et al, 2009). Aphakia mice lack both VMAT2 and DAT as seen by both in situ hybridization and PCR (Table 2.1) (Smits et al, 2005).…”