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The Journal of Neuroscience, May 2, 2007, 27(18):4799-4809; doi:10.1523/JNEUROSCI.5647-06.2007

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Cellular/Molecular
Constitutive Ret Activity in Knock-In Multiple Endocrine Neoplasia Type B Mice Induces Profound Elevation of Brain Dopamine Concentration via Enhanced Synthesis and Increases the Number of TH-Positive Cells in the Substantia Nigra

Jelena Mijatovic,^1 * Mikko Airavaara,^1 * Anu Planken,² Petri Auvinen,² Atso Raasmaja,¹ T. Petteri Piepponen,¹ Frank Costantini,³ Liisa Ahtee,¹ and Mart Saarma²

¹Division of Pharmacology and Toxicology, Faculty of Pharmacy, and ²Institute of Biotechnology, Viikki Biocenter, University of Helsinki, FIN-00014 Helsinki, Finland, and ³Department of Genetics and Development, Columbia University Medical Center, New York, New York 10032

Correspondence should be addressed to Jelena Mijatovic, Division of Pharmacology and Toxicology, Faculty of Pharmacy, P.O. Box 56, FIN-00014, University of Helsinki, Finland. Email: jelena.mijatovic{at}helsinki.fi

Ret is the common signaling receptor for glial cell line-derived neurotrophic factor (GDNF) and other ligands of the GDNF family that have potent effects on brain dopaminergic neurons. The Met918Thr mutation leads to constitutive activity of Ret receptor tyrosine kinase, causing the cancer syndrome called multiple endocrine neoplasia type B (MEN2B). We used knock-in MEN2B mice with the Ret-MEN2B mutation to study the effects of constitutive Ret activity on the brain dopaminergic system and found robustly increased concentrations of dopamine (DA) and its metabolites in the striatum, cortex, and hypothalamus. The concentrations of brain serotonin were not affected and those of noradrenaline were slightly increased only in the lower brainstem. Tyrosine hydroxylase (TH) protein levels were increased in the striatum and substantia nigra/ventral tegmental area (SN/VTA), and TH mRNA levels were increased in SN/VTA of MEN2B mice, suggesting that constitutive Ret activity increases DA levels by increasing its synthesis. Also, the striatal DA transporter protein levels in the MEN2B mice were increased, which agrees with increased sensitivity of these mice to the stimulatory effects of cocaine. In the SN pars compacta of homozygous MEN2B mice, we found a 26% increase in the number of TH-positive cells, but no differences were found in the VTA. Thus, we show here that the constitutive Ret activity in mice is sufficient to increase the number of dopaminergic neurons and leads to profound elevation of brain DA concentration. These data clearly suggest that Ret activity per se can have a direct biological function that actively changes and shapes the brain dopaminergic system.

Key words: Ret receptor; glial cell line-derived neurotrophic factor; brain dopamine; tyrosine hydroxylase; dopamine transporter; multiple endocrine neoplasia

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Received June 22, 2006; revised March 6, 2007; accepted March 16, 2007.

Correspondence should be addressed to Jelena Mijatovic, Division of Pharmacology and Toxicology, Faculty of Pharmacy, P.O. Box 56, FIN-00014, University of Helsinki, Finland. Email: jelena.mijatovic{at}helsinki.fi

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