The dopamine D2 receptor regulates the development of dopaminergic neurons via extracellular signal-regulated kinase and Nurr1 activation.
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.
Kim
Sung Yul
SY
School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, South Korea.
Choi
Kyou Chan
KC
Chang
Min Seok
MS
Kim
Myoung Hwan
MH
Kim
Sa Yong
SY
Na
Young-Soon
YS
Lee
Jong Eun
JE
Jin
Byung Kwan
BK
Lee
Bong-Hee
BH
Baik
Ja-Hyun
JH
D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D008636:Mesencephalon / Q000166:cytology / Q000502:physiology; D051379:Mice; D009474:Neurons / Q000166:cytology* / Q000502:physiology*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D004268:DNA-Binding Proteins; C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D017448:Receptors, Dopamine D2; D014157:Transcription Factors; D048049:Extracellular Signal-Regulated MAP Kinases; D004298:Dopamine