Midbrain dopaminergic (mDA) neurons critically control voluntary movement, reward, and mood-related behaviors, and their degeneration/dysfunction is associated with major brain disorders such as Parkinson's disease (PD) and schizophrenia. In-depth understanding of molecular pathways underlying mDA neuron development will be crucial for effective therapeutic approaches of these diseases. To investigate the developmental mechanisms of the DA and noradrenaline (NA) systems, we previously proposed to study the transcriptional regulation of two hallmark genes encoding tyrosine hydroxylase (TH) and dopamine ?-hydroxylase (DBH), enzymes that catalyze the conversion of tyrosine to L-dopa, and of DA to NA, respectively. We have delineated the transcriptional mechanisms of TH and DBH gene expression and identified several key transcription factors that critically control these neuronal developments. In particular, we found that functional knockout of the homeodomain transcription factor Pitx3 uniquely leads to specific degeneration of A9 DA neurons of the substantia nigra and their nigrostriatal pathway, mimicking the pathological PD condition. Based on these progresses, we will focus on the transcriptional regulatory cascades/pathways during mDA neuronal development by focusing on further elucidation of the mechanisms of action and regulation of Pitx3 during different stages of mDA neuron development. We will define their functional roles, identify downstream targets, investigate the mechanisms of action, and their potential roles for A9-specific vulnerability. In addition, we will identity upstream regulator(s) of Pitx3 gene expression and how these factors functionally interplay with each other during mDA development for regulating neurogenesis, precursor specification, and mDA terminal differentiation. Finally, using our DA-specific gene delivery method, we will test if gene therapy approach of these key factors may ameliorate behavioral symptoms in PD animal model(s). Our proposed experiments will not only shed further insights into the molecular pathways of mDA neuron development but also translate into the study of related disease mechanisms as well as open the door to novel therapeutic approaches.

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Midbrain dopamine (mDA) neurons play critical roles in the regulation of voluntary movement, emotion, and reward-related behavior;their degeneration and/or dysfunction are associated with major brain disorders such as Parkinson's disease (PD), schizophrenia, and drug addiction. Based on our previous results indicating the critical role of Pitx3 for A9 mDA neuron development/maintenance, the proposed studies are aimed at elucidating the regulatory cascades/networks of the transcription factor Pitx3 during different stages of mDA neuron development. These studies will not only identify the molecular pathways underlying specification and maintenance of these neurons but may also provide novel insights for disease mechanisms and development of effective therapeutic approaches for related brain disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BDCN-J (03))
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Beckel-Mitchener, Andrea C
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Mclean Hospital
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Hong, Seok Jong; Huh, Yang Hoon; Leung, Amanda et al. (2011) Transcription factor AP-2? regulates the neurotransmitter phenotype and maturation of chromaffin cells. Mol Cell Neurosci 46:245-51
Huh, Youngbuhm; Oh, Myung S; Leblanc, Pierre et al. (2010) Gene transfer in the nervous system and implications for transsynaptic neuronal tracing. Expert Opin Biol Ther 10:763-72
Kim, Dohoon; Kim, Chun-Hyung; Moon, Jung-Il et al. (2009) Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell 4:472-6
Chung, Sangmi; Leung, Amanda; Han, Baek-Soo et al. (2009) Wnt1-lmx1a forms a novel autoregulatory loop and controls midbrain dopaminergic differentiation synergistically with the SHH-FoxA2 pathway. Cell Stem Cell 5:646-58
Oh, M S; Hong, S J; Huh, Y et al. (2009) Expression of transgenes in midbrain dopamine neurons using the tyrosine hydroxylase promoter. Gene Ther 16:437-40
Hong, Seok Jong; Chae, Han; Lardaro, Thomas et al. (2008) Trim11 increases expression of dopamine beta-hydroxylase gene by interacting with Phox2b. Biochem Biophys Res Commun 368:650-5
Ardayfio, Paul; Moon, Jisook; Leung, Ka Ka Amanda et al. (2008) Impaired learning and memory in Pitx3 deficient aphakia mice: a genetic model for striatum-dependent cognitive symptoms in Parkinson's disease. Neurobiol Dis 31:406-12
Han, Baek-Soo; Iacovitti, Lorraine; Katano, Taku et al. (2008) Expression of the LRRK2 gene in the midbrain dopaminergic neurons of the substantia nigra. Neurosci Lett 442:190-4
Hong, Seok Jong; Choi, Hyun Jin; Hong, Sunghoi et al. (2008) Transcription factor GATA-3 regulates the transcriptional activity of dopamine beta-hydroxylase by interacting with Sp1 and AP4. Neurochem Res 33:1821-31