The dopamine D2 receptor regulates the development of dopaminergic neurons via extracellular signal-regulated kinase and Nurr1 activation

Yul Kim Sung, Chan Choi Kyou, Seok Chang Min, Hwan Kim Myoung, Yong Kim Sa, Young Soon Na, Jongeun Lee, Kwan Jin Byung, Bong Hee Lee, Ja Hyun Baik

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Abstract

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 D 2 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 D 2R-/- 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.

Original languageEnglish
Pages (from-to)4567-4576
Number of pages10
JournalJournal of Neuroscience
Volume26
Issue number17
DOIs
Publication statusPublished - 2006 Sep 7

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Dopamine D2 Receptors
Dopaminergic Neurons
Extracellular Signal-Regulated MAP Kinases
Tyrosine 3-Monooxygenase
Reporter Genes
Response Elements
Neurons
Nuclear Receptor Subfamily 4, Group A, Member 2
Quinpirole
Mesencephalon
Luciferases
Reverse Transcription
Dopamine
Polymerase Chain Reaction

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Sung, Yul Kim ; Kyou, Chan Choi ; Min, Seok Chang ; Myoung, Hwan Kim ; Sa, Yong Kim ; Na, Young Soon ; Lee, Jongeun ; Byung, Kwan Jin ; Lee, Bong Hee ; Baik, Ja Hyun. / The dopamine D2 receptor regulates the development of dopaminergic neurons via extracellular signal-regulated kinase and Nurr1 activation. In: Journal of Neuroscience. 2006 ; Vol. 26, No. 17. pp. 4567-4576.
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abstract = "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 D 2 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 D 2R-/- 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.",
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The dopamine D2 receptor regulates the development of dopaminergic neurons via extracellular signal-regulated kinase and Nurr1 activation. / Sung, Yul Kim; Kyou, Chan Choi; Min, Seok Chang; Myoung, Hwan Kim; Sa, Yong Kim; Na, Young Soon; Lee, Jongeun; Byung, Kwan Jin; Lee, Bong Hee; Baik, Ja Hyun.

In: Journal of Neuroscience, Vol. 26, No. 17, 07.09.2006, p. 4567-4576.

Research output: Contribution to journalArticle

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AU - Sung, Yul Kim

AU - Kyou, Chan Choi

AU - Min, Seok Chang

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AU - Sa, Yong Kim

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AU - Baik, Ja Hyun

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