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KMID : 0380020050200050363
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Korean Journal of Biotechnology and Bioengineering
2005 Volume.20 No. 5 p.363 ~ p.370
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Induction of Midbrain Dopaminergic Phenotype in Nurr 1-Overexpressing Human Neural Stem Cells
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Kim Han-Jip
Lee Hak-Sup
Kim Hyun-Chang
Min Churl-Ki
Lee Myung-Ae
Kim Seung-Up
Han Jin
Youm Jae-Boum
Kim Na-Ri
Park Won-Sun
Kim Tae-Ho
Kim Eui-Yong
Han Il-Yong
Choi In-Soon
Joo Hyun
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Abstract
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Neural stem cells (NSCs) of the central nervous system (CNS) have raised a great interest not only for their importance in basic neural development but also for their therapeutic potentials in neurologically degenerative diseases such as Parkinson’s, Alzheimer and stroke. During the CNS development, two molecular cascades determine specification of midbrain dopamine system. In one pathway, FGF-8, sonic hedgehog and transcription factor Nurr1 specify dopamine neurotransmitter phenotype. In the other, transcription factors are required for induction of dopaminergic neurons. In Nurr1 knockout mouse, tyrosine hydroxylase (TH) positive cells fail to appear in substantia nigra, indicating that Nurr1 is essential in specification of dopaminergic cell phenotype. In this study, we used the immortalized human NSCs retrovirally transduced with Nurr1 gene to probe the Nurr1 mediated mechanism to induce dopamine phenotype. While Nurr1 over-expression alone did not generate dopamine phenotype in NSCs, applications of retinoid and forskolin induced expression of TH and AADC mRNAs. In addition, co-cultures of Nurr1 expressing NSCs with human astrocytes induced a marked increase of TH expression. In this co-culture system, the addition of retinoid and forskolin dramatically increased expression of TH. These results indicate that the immortalized human NSCs with Nurr1 gene could have a clinical utility for cell replacement for the Parkinson patients.
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KEYWORD
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Nurr 1, dopamine, Parkinson`s disease, tyrosine hydroxylase, CNS, brain disease, neural stem cell
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