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

Hwang, Dong-Youn and Hong, Sunghoi and Jeong, Joo-Won and Choi, Sangdun and Kim, Hansoo and Kim, Jangwoo and Kim, Kwang-Soo (2009) Vesicular monoamine transporter 2 and dopamine transporter are molecular targets of Pitx3 in the ventral midbrain dopamine neurons. Journal of Neurochemistry, 111 (5). pp. 1202-1212. ISSN 0022-3042. https://resolver.caltech.edu/CaltechAUTHORS:20091201-084307989

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1111/j.1471-4159.2009.06404.x DOIArticle
http://www3.interscience.wiley.com/cgi-bin/fulltext/122608154/HTMLSTARTWPublisherArticle
Additional Information:© 2009 International Society for Neurochemistry. Received June 27, 2009; revised manuscript received September 14, 2009; accepted September 15, 2009. This work was supported by NIH grants MH48866, DC006501, Michael J Fox Foundation for Parkinson’s Research, and International Grants from Brain and Stem Cell Research Centers (SC5130 & SC5170) funded by the Ministry of Education, Science and Technology, the Republic of Korea. The authors declare no conflicts of interest.
Funders:
Funding AgencyGrant Number
NIHMH48866
NIHDC006501
Michael J Fox Foundation for Parkinson’s ResearchUNSPECIFIED
Brain and Stem Cell Research CentersSC5130
Brain and Stem Cell Research CentersSC5170
Ministry of Education, Science and Technology Republic (Korea)UNSPECIFIED
Subject Keywords:aphakia mice, dopamine neuron, Parkinson's disease, Pitx3 • substantia nigra pars compacta
Issue or Number:5
Record Number:CaltechAUTHORS:20091201-084307989
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20091201-084307989
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:16847
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:07 Dec 2009 19:53
Last Modified:03 Oct 2019 01:18

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