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 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.