Striatal-enriched protein tyrosine phosphatase regulates dopaminergic neuronal development via extracellular signal-regulated kinase signaling.
The striatal-enriched protein tyrosine phosphatase (STEP) is highly expressed within dopaminoceptive neurons, suggesting the possibility that STEP may interact with dopaminergic signaling. We have previously shown that signaling through dopamine D2 receptor (D2R)-mediated extracellular signal-regulated kinase (ERK) activation plays a critical role in mesencephalic dopaminergic neuronal development. Here, we investigate the role of STEP in D2R-mediated ERK signaling, especially in dopaminergic neuronal development. Analyses of developmental expression of STEP and tyrosine hydroxylase (TH) in mouse brain demonstrate that STEP- and TH-positive cells are co-localized in the substantia nigra compacta of brains of postnatal 8-day-old mice, displaying STEP expression in dopaminergic neurons at this stage. Stereological analysis demonstrates a dynamic change in the number of STEP-expressing cells from midbrain to striatum during development in WT mice and significantly decreased number of STEP-expressing cells in mice lacking D2R (D2R(-/-) mice). The knockdown of STEP expression by treatment with oligomeric STEP siRNA significantly decreased the number of mesencephalic TH cells and inhibited D2R-mediated development of dopaminergic neurons on primary mesencephalic culture from WT mice, but not in primary cultures from D2R(-/-) mice. Furthermore, knockdown of STEP expression perturbed D2R-mediated ERK signaling in dopaminergic neuronal cells from WT mice, but not from D2R(-/-) mice. These results suggest that STEP is an important mediator in the dopamine D2R-mediated activation of ERK signaling and in the regulation of dopaminergic neuronal development.
Kim
Sung Yul
SY
Molecular Neurobiology Laboratory, School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, South Korea.
Lee
Hyo Jin
HJ
Kim
Yong Nyun
YN
Yoon
Sehyoun
S
Lee
Jong Eun
JE
Sun
Woong
W
Choi
Eui-Ju
EJ
Baik
Ja-Hyun
JH
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D002452:Cell Count; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D007150:Immunohistochemistry; D051379:Mice; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D011954:Receptors, Dopamine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D034741:RNA, Small Interfering; D011954:Receptors, Dopamine; D048049:Extracellular Signal-Regulated MAP Kinases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C082101:Ptpn5 protein, mouse; D004298:Dopamine