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Sharon K. Michelhaugh, Ph.D.
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RESEARCH INTERESTS:
Regulation of Dopamine Phenotype by the Transcription Factor Nurr1
Nurr1 is a transcription factor that is specifically expressed in dopamine neurons of the ventral midbrain and plays a vital role in the development of the dopamine phenotype in those neurons. Nurr1’s profound effect on dopamine neuron function and phenotype is demonstrated most clearly by studies of homozygotic nurr1 knockout mice. Disruption of the NR4A2 gene that encodes nurr1 is lethal. Nurr1(-/-) mice die one day after birth and never synthesize dopamine or express tyrosine hydroxylase (TH) or dopamine transporter (DAT) in the midbrain.
In addition to the requirement of nurr1 for normal development of dopamine phenotype, nurr1 is also necessary for the maintenance of dopamine phenotype and therefore dopaminergic neurotransmission. Nurr1 directly regulates expression of the TH, DAT and GTP cyclohydrolase (GTPCH) genes. Studies of post-mortem human midbrain have revealed decreases of nurr1 expression and highly correlated decreases of TH, DAT and GTPCH throughout the course of normal human aging. In parallel, decreases of TH and DAT are also found in the midbrain of aged rats. In both aged humans and rats, the number of neurons in the midbrain is not reduced. Therefore, the diminished TH and DAT expression indicates a loss of dopaminergic phenotype in midbrain neurons, and may be a consequence of reduced nurr1 expression. This loss of dopaminergic phenotype in the midbrain produces a reduction in dopaminergic function in the striatum that has been positively correlated to age-related cognitive deficits in humans and decreased locomotor behavior in rats.
Studies are underway to further define the role of nurr1 in the regulation of dopamine phenotype in the SK-N-AS human neuroblastoma cell line. SK-N-AS cells endogenously express nurr1, TH, DAT and GTPCH, making them a uniquely suitable model for human dopamine neurons.
Nurr1 immunostaining in human midbrain dopamine neurons. The arrow is pointing to a nucleus with robust expression of nurr1. The asterisk indicates the neuromelanin, which is a marker of midbrain dopamine neurons. The scale bar is 25 microns.
Selected Publications:
Jun Wang, Sharon K. Michelhaugh and Michael J. Bannon. Valproate robustly increases Sp transcription factor-mediated expression of the dopamine transporter gene within dopamine cells. European Journal of Neuroscience; 25(7):1982-6, 2007.
Sharon K. Michelhaugh, Henrikas Vaitkevicius, Jun Wang, Mohamad Bouhamdan, Alexys R. Krieg, Jennifer L. Walker, Varsha Mendiratta and Michael J. Bannon. Dopamine neurons express multiple isoforms of the nuclear receptor nurr1 with diminished transcriptional activity. Journal of Neurochemistry, 95(5):1342-50, 2005.
Michael J. Bannon, Barb Pruetz, Amy B. Manning-Bog, Christopher J. Whitty, Sharon K. Michelhaugh, Paola Sacchetti, James G. Granneman, Deborah C. Mash, and Carl J. Schmidt. Decreased expression of the transcription factor NURR1 in dopamine neurons
of cocaine abusers. Proc. Natl. Acad. Sci. USA, 99(9):6382-85, 2002.
Sharon K. Michelhaugh, Carolyn Fiskerstrand, Elizabeth Lovejoy, Michael J. Bannon and John P. Quinn. The dopamine transporter gene (SLC6A3) variable number of tandem repeats domain enhances transcription in dopamine neurons. Journal of Neurochemistry, 79(5):1033-38, 2001.
Michael J. Bannon, Sharon K. Michelhaugh, Jun Wang and Paola Sacchetti: The human dopamine transporter gene: Gene organization, transcriptional regulation, and potential involvement in neuropsychiatric disorders. European Neuropsychopharmacology, 11(6):449-55, 2001.
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