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The Journal of Neuroscience, April 26, 2006, 26(17):4567-4576; doi:10.1523/JNEUROSCI.5236-05.2006

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Neurobiology of Disease
The Dopamine D₂ Receptor Regulates the Development of Dopaminergic Neurons via Extracellular Signal-Regulated Kinase and Nurr1 Activation

Sung Yul Kim,^1 * Kyou Chan Choi,^1,2 * Min Seok Chang,¹ Myoung Hwan Kim,^1,2 Sa Yong Kim,¹ Young-Soon Na,¹ Jong Eun Lee,² Byung Kwan Jin,³ Bong-Hee Lee,⁴ and Ja-Hyun Baik¹

¹School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, South Korea, ²Brain Korea 21 Project for Medical Science, College of Medicine, Yonsei University, Seoul 120-752, South Korea, ³Neuroscience Graduate Program, Brain Disease Research Center, Ajou University School of Medicine, Suwon 443-721, South Korea, and ⁴Department of Anatomy, Medical School, Cheju National University, Cheju 690-756, South Korea

Correspondence should be addressed to Dr. Ja-Hyun Baik, Molecular Neurobiology Laboratory, School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, South Korea. Email: jahyunb{at}korea.ac.kr

Because the dopaminergic pathways in the midbrain have been closely associated with serious neuropsychiatric disorders, the elucidation of the mechanisms underlying dopaminergic neuronal development should provide some important clues for related disorders. In mice lacking the dopamine D₂ receptor (D₂R–/–), stereological cell counting analysis showed that the number of mesencephalic tyrosine hydroxylase (TH) cells was significantly low during ontogeny, compared with that observed in wild-type (WT) mice, thereby indicating an alteration in dopaminergic neuronal development in the absence of D₂R. The results of immunohistochemical and reverse transcription-PCR analyses revealed that the expression of Nurr1, an orphan nuclear receptor, as well as Ptx3 expression, was selectively reduced in D₂R–/– mice during the embryonic stage. A reporter gene assay using the Nur response element linked to the luciferase reporter gene indicated that the stimulation of D₂R results in the activation of the Nurr1-mediated reporter gene. This D₂R-mediated Nur response element-dependent transcriptional activity was regulated via the activation of extracellular signal-regulated kinase (ERK). Furthermore, quinpirole treatment was shown to elicit an increase in the number of TH-positive neurons, as well as the neuritic extension of TH neurons, coupled with ERK activation and Nurr1 activation in the TH-positive neurons in primary mesencephalic cultures from WT mice. However, this regulation was not detected in the D₂R–/– mice. These results suggest that signaling through D₂R in association with Nurr1 using ERK, plays a critical role in mesencephalic dopaminergic neuronal development.

Key words: dopamine receptor; Nurr1; ERK; tyrosine hydroxylase; dopaminergic neurons; development

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Received Dec. 8, 2005; revised March 8, 2006; accepted March 12, 2006.

Correspondence should be addressed to Dr. Ja-Hyun Baik, Molecular Neurobiology Laboratory, School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, South Korea. Email: jahyunb{at}korea.ac.kr

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