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The Journal of Neuroscience, October 25, 2006, 26(43):11230-11238; doi:10.1523/JNEUROSCI.1876-06.2006

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Development/Plasticity/Repair
RET Is Dispensable for Maintenance of Midbrain Dopaminergic Neurons in Adult Mice

Sanjay Jain,¹ Judith P. Golden,² David Wozniak,³ Elizabeth Pehek,⁵ Eugene M. Johnson, Jr,^2,4 and Jeffrey Milbrandt⁴

¹Department of Medicine, Renal Division, and Departments of ²Molecular Biology and Pharmacology, ³Psychiatry, ⁴Pathology, and Neurology and HOPE Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110, and ⁵Departments of Psychiatry and Neuroscience, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106

Correspondence should be addressed to Sanjay Jain at the above address, Email: sjain22{at}wustl.edu; or Eugene M. Johnson Jr, Email: eugene.johnson{at}wustl.edu; or Jeffery Milbrandt, Email: jeff{at}pathbox.wustl.edu

Glial cell-line derived neurotrophic factor (GDNF)-mediated RET tyrosine kinase signaling is implicated in the survival of several PNS and CNS neuronal populations that are important in the pathogenesis of several disorders including Parkinson's disease and drug addiction. However, it has been difficult to study these processes and the physiological importance of this pathway in adult mice because of the neonatal lethality of Gdnf and Ret null mice. We report successful creation of RET conditional reporter mice to investigate postnatal physiologic roles of RET and monitor the fate of RET-expressing cell types. To delete RET specifically in dopaminergic neurons and determine the physiologic requirement of RET in the maintenance of substantia nigra compacta (SNC) and ventral tegmental area (VTA), we bred the RET conditional mice with mice that specifically express Cre from the dopamine transporter (Dat) locus. A detailed morphometric and biochemical analysis including dopaminergic neuron number and size in SNC and VTA, and fiber density in the striatum and nucleus accumbens, and dopamine levels indicate that RET is not required for providing global trophic support to midbrain dopaminergic neurons in adult mice. Furthermore, RET deficiency in these neurons does not cause major sensorimotor abnormalities. Hence our results support the idea that RET signaling is not critical for the normal physiology of the SNC and VTA in adult mice.

Key words: RET; GDNF; Parkinson; addiction; dopamine; RTK

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Received May 3, 2006; revised Aug. 18, 2006; accepted Sept. 14, 2006.

Correspondence should be addressed to Sanjay Jain at the above address, Email: sjain22{at}wustl.edu; or Eugene M. Johnson Jr, Email: eugene.johnson{at}wustl.edu; or Jeffery Milbrandt, Email: jeff{at}pathbox.wustl.edu

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