Dopaminergic neuronal differentiation from rat embryonic neural precursors by Nurr1 overexpression

In vitro expanded CNS precursors could provide a renewable source of dopamine (DA) neurons for cell therapy in Parkinson's disease. Functional DA neurons have been derived previously from early midbrain precursors. Here we demonstrate the ability of Nurr1, a nuclear orphan receptor essential for midbrain DA neuron development in vivo, to induce dopaminergic differentiation in naïve CNS precursors in vitro. Independent of gestational age or brain region of origin, Nurr1‐induced precursors expressed dopaminergic markers and exhibited depolarization‐evoked DA release in vitro. However, these cells were less mature and secreted lower levels of DA than those derived from mesencephalic precursors. Transplantation of Nurr1‐induced DA neuron precursors resulted in limited survival and in vivo differentiation. No behavioral improvement in apomorphine‐induced rotation scores was observed. These results demonstrate that Nurr1 induces dopaminergic features in naïve CNS precursors in vitro. However, additional factors will be required to achieve in vivo function and to unravel the full potential of neural precursors for cell therapy in Parkinson's disease.

[1]  Ji-yeon Lee,et al.  Erythropoietin and bone morphogenetic protein 7 mediate ascorbate‐induced dopaminergic differentiation from embryonic mesencephalic precursors , 2003, Neuroreport.

[2]  Kwang-Soo Kim,et al.  Genetic engineering of mouse embryonic stem cells by Nurr1 enhances differentiation and maturation into dopaminergic neurons , 2002, The European journal of neuroscience.

[3]  R. McKay,et al.  Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease , 2002, Nature.

[4]  A. Nieoullon.  Dopamine and the regulation of cognition and attention , 2002, Progress in Neurobiology.

[5]  L. Olson,et al.  Orphan Nuclear Receptor Nurr1 Is Essential for Ret Expression in Midbrain Dopamine Neurons and in the Brain Stem , 2001, Molecular and Cellular Neuroscience.

[6]  B. Joseph,et al.  Induction of Cell Cycle Arrest and Morphological Differentiation by Nurr1 and Retinoids in Dopamine MN9D Cells* , 2001, The Journal of Biological Chemistry.

[7]  F. Cicchetti,et al.  Cell implantation therapies for Parkinson's disease using neural stem, transgenic or xenogeneic donor cells. , 2001, Parkinsonism & related disorders.

[8]  S. Nam,et al.  Generation of fusion genes carrying drug resistance, green fluorescent protein, and herpes simplex virus thymidine kinase genes in a single cistron. , 2001, Molecules and cells.

[9]  R. McKay,et al.  Ascorbic acid increases the yield of dopaminergic neurons derived from basic fibroblast growth factor expanded mesencephalic precursors , 2001, Journal of neurochemistry.

[10]  M. Palkovits,et al.  Nigrostriatal innervation is preserved in Nurr1-null mice, although dopaminergic neuron precursors are arrested from terminal differentiation. , 2000, Brain research. Molecular brain research.

[11]  T. Iwawaki,et al.  Identification of a potential nurr1 response element that activates the tyrosine hydroxylase gene promoter in cultured cells. , 2000, Biochemical and biophysical research communications.

[12]  A. Björklund,et al.  Cell replacement therapies for central nervous system disorders , 2000, Nature Neuroscience.

[13]  Marten P. Smidt,et al.  A second independent pathway for development of mesencephalic dopaminergic neurons requires Lmx1b , 2000, Nature Neuroscience.

[14]  S. Hyman,et al.  Addiction, Dopamine, and the Molecular Mechanisms of Memory , 2000, Neuron.

[15]  P. Brundin,et al.  Intrastriatal Ventral Mesencephalic Xenografts of Porcine Tissue in Rats: Immune Responses and Functional Effects , 2000, Cell transplantation.

[16]  Ornella Rimoldi,et al.  Dopamine release from nigral transplants visualized in vivo in a Parkinson's patient , 1999, Nature Neuroscience.

[17]  C. Olanow,et al.  Use of placebo surgery in controlled trials of a cellular-based therapy for Parkinson's disease. , 1999, The New England journal of medicine.

[18]  F. Gage,et al.  Nurr1, an orphan nuclear receptor, is a transcriptional activator of endogenous tyrosine hydroxylase in neural progenitor cells derived from the adult brain. , 1999, Development.

[19]  E. Snyder,et al.  Induction of a midbrain dopaminergic phenotype in Nurr1-overexpressing neural stem cells by type 1 astrocytes , 1999, Nature Biotechnology.

[20]  D. Lipovšek,et al.  Smartbombs and cloaking devices , 1999, Nature Biotechnology.

[21]  R. McKay,et al.  Reply to “Survival of expanded dopaminergic precursors is critical for clinical trials” , 1998, Nature Neuroscience.

[22]  R. McKay,et al.  Transplantation of expanded mesencephalic precursors leads to recovery in parkinsonian rats , 1998, Nature Neuroscience.

[23]  J. Rubenstein,et al.  FGF and Shh Signals Control Dopaminergic and Serotonergic Cell Fate in the Anterior Neural Plate , 1998, Cell.

[24]  M. Palkovits,et al.  Dopamine Biosynthesis Is Selectively Abolished in Substantia Nigra/Ventral Tegmental Area but Not in Hypothalamic Neurons in Mice with Targeted Disruption of the Nurr1 Gene , 1998, Molecular and Cellular Neuroscience.

[25]  M. Smidt,et al.  Nurr1 is essential for the induction of the dopaminergic phenotype and the survival of ventral mesencephalic late dopaminergic precursor neurons. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[26]  E. Clarkson,et al.  Growth factors improve immediate survival of embryonic dopamine neurons after transplantation into rats , 1998, Brain Research.

[27]  G Wolterink,et al.  A homeodomain gene Ptx3 has highly restricted brain expression in mesencephalic dopaminergic neurons. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[28]  A. Gurney,et al.  Control of Cell Pattern in the Neural Tube by the Zinc Finger Transcription Factor and Oncogene Gli-1 , 1997, Neuron.

[29]  B J Hoffer,et al.  Dopamine neuron agenesis in Nurr1-deficient mice. , 1997, Science.

[30]  R. McKay,et al.  Stem Cells in the Central Nervous System , 1997, Science.

[31]  C. Spenger,et al.  Noninvasive dopamine determination by reversed phase HPLC in the medium of free-floating roller tube cultures of rat fetal ventral mesencephalon: A tool to assess dopaminergic tissue prior to grafting , 1996, Brain Research Bulletin.

[32]  R. McKay,et al.  Single factors direct the differentiation of stem cells from the fetal and adult central nervous system. , 1996, Genes & development.

[33]  A. Björklund,et al.  Glial cell line-derived neurotrophic factor increases survival, growth and function of intrastriatal fetal nigral dopaminergic grafts. , 1996, Neuroscience.

[34]  R. Mulligan,et al.  A stable human-derived packaging cell line for production of high titer retrovirus/vesicular stomatitis virus G pseudotypes. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[35]  T. Deacon,et al.  Xenotransplantation of Porcine Fetal Ventral Mesencephalon in a Rat Model of Parkinson's Disease: Functional Recovery and Graft Morphology , 1996, Experimental Neurology.

[36]  C. Olanow,et al.  Fetal nigral transplantation as a therapy for Parkinson's disease , 1996, Trends in Neurosciences.

[37]  K. O’Malley,et al.  Overexpression of Bcl-2 in a murine dopaminergic neuronal cell line leads to neurite outgrowth , 1996, Neuroscience Letters.

[38]  A. McMahon,et al.  Induction of dopaminergic neuron phenotype in the midbrain by Sonic hedgehog protein , 1995, Nature Medicine.

[39]  Marc Tessier-Lavigne,et al.  Induction of midbrain dopaminergic neurons by Sonic hedgehog , 1995, Neuron.

[40]  M. Tessier-Lavigne,et al.  Control of neuronal diversity by the floor plate: Contact-mediated induction of midbrain dopaminergic neurons , 1995, Cell.

[41]  A M Graybiel,et al.  The basal ganglia and adaptive motor control. , 1994, Science.

[42]  A. Björklund.  Better cells for brain repair , 1993, Nature.

[43]  L. Grégoire,et al.  Correlation of functional recovery after a 6-hydroxydopamine lesion with survival of grafted fetal neurons and release of dopamine in the striatum of the rat , 1991, Neuroscience.

[44]  J. Barker,et al.  Specific Reinnervation of Lesioned Mouse Striatum by Grafted Mesencephalic Dopaminergic Neurons , 1991, The European journal of neuroscience.

[45]  INTERNATIONAL SOCIETY FOR NEUROCHEMISTRY , 1976 .

[46]  F. Gage,et al.  Stem cells of the central nervous system. , 1998, Current opinion in neurobiology.