Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease


Parkinson's disease is a widespread condition caused by the loss of midbrain neurons that synthesize the neurotransmitter dopamine. Cells derived from the fetal midbrain can modify the course of the disease, but they are an inadequate source of dopamine-synthesizing neurons because their ability to generate these neurons is unstable. In contrast, embryonic stem (ES) cells proliferate extensively and can generate dopamine neurons. If ES cells are to become the basis for cell therapies, we must develop methods of enriching for the cell of interest and demonstrate that these cells show functions that will assist in treating the disease. Here we show that a highly enriched population of midbrain neural stem cells can be derived from mouse ES cells. The dopamine neurons generated by these stem cells show electrophysiological and behavioural properties expected of neurons from the midbrain. Our results encourage the use of ES cells in cell-replacement therapy for Parkinson's disease.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Properties of neural precursors derived from Nurr1 ES cells.
Figure 2: Characterization of TH+ neurons derived from Nurr1-transfected ES cells.
Figure 3: Nurr1 ES cells integrate into the striatum of hemiparkinsonian rats.
Figure 4: Electrophysiological properties of TH+ neurons.
Figure 5: Behavioural effects of grafted Nurr1 ES cells.


  1. 1

    Studer, L., Tabar, V. & McKay, R. D. Transplantation of expanded mesencephalic precursors leads to recovery in parkinsonian rats. Nature Neurosci. 1, 290–295 (1998)

    CAS  Article  Google Scholar 

  2. 2

    Sanchez-Pernaute, R., Studer, L., Bankiewicz, K. S., Major, E. O. & McKay, R. D. In vitro generation and transplantation of precursor-derived human dopamine neurons. J. Neurosci. Res. 65, 284–288 (2001)

    CAS  Article  Google Scholar 

  3. 3

    Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998)

    ADS  CAS  Article  Google Scholar 

  4. 4

    Shamblott, M. J. et al. Derivation of pluripotent stem cells from cultured human primordial germ cells. Proc. Natl Acad. Sci. USA 95, 13726–13731 (1998)

    ADS  CAS  Article  Google Scholar 

  5. 5

    McDonald, J. W. et al. Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord. Nature Med. 5, 1410–1412 (1999)

    CAS  Article  Google Scholar 

  6. 6

    Rideout, W. M. III, Hochedlinger, K., Kyba, M., Daley, G. & Jaenisch, R. Correction of a genetic defect by nuclear transplantation and combined cell and gene therapy. Cell 109, 17–27 (2002)

    CAS  Article  Google Scholar 

  7. 7

    Kyba, M., Perlingeiro, R. C. R. & Daley, G. Q. HoxB4 confers definitive lymphoid–myeloid engraftment potential on embryonic stem cell and yolk sac hematopoietic progenitors. Cell 109, 29–37 (2002)

    CAS  Article  Google Scholar 

  8. 8

    Lee, S. H., Lumelsky, N., Auerbach, J. M. & McKay, R. D. Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells. Nature Biotechnol. 18, 675–679 (2000)

    CAS  Article  Google Scholar 

  9. 9

    Okabe, S., Forsberg-Nilsson, K., Spiro, A. C., Segal, M. & McKay, R. D. Development of neuronal precursor cells and functional postmitotic neurons from embryonic stem cells in vitro. Mech. Dev. 59, 89–102 (1996)

    CAS  Article  Google Scholar 

  10. 10

    Wallen, A. et al. Fate of mesencephalic AHD2-expressing dopamine progenitor cells in NURR1 mutant mice. Exp. Cell. Res. 253, 737–746 (1999)

    CAS  Article  Google Scholar 

  11. 11

    Zetterstrom, R. H. et al. Dopamine neuron agenesis in Nurr1-deficient mice. Science 276, 248–250 (1997)

    CAS  Article  Google Scholar 

  12. 12

    Saucedo-Cardenas, O. et al. Nurr1 is essential for the induction of the dopaminergic phenotype and the survival of ventral mesencephalic late dopaminergic precursor neurons. Proc. Natl Acad. Sci. USA 95, 4013–4018 (1998)

    ADS  CAS  Article  Google Scholar 

  13. 13

    Le, W. et al. Selective agenesis of mesencephalic dopaminergic neurons in Nurr1-deficient mice. Exp. Neurol. 159, 451–458 (1999)

    CAS  Article  Google Scholar 

  14. 14

    Lumelsky, N. et al. Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets. Science 292, 1389–1394 (2001)

    ADS  CAS  Article  Google Scholar 

  15. 15

    Bader, A., Al-Dubai, H. & Weitzer, G. Leukemia inhibitory factor modulates cardiogenesis in embryoid bodies in opposite fashions. Circ. Res. 86, 787–794 (2000)

    CAS  Article  Google Scholar 

  16. 16

    Molne, M. et al. Early cortical precursors do not undergo LIF-mediated astrocytic differentiation. J. Neurosci. Res. 59, 301–311 (2000)

    ADS  CAS  Article  Google Scholar 

  17. 17

    Offield, M. F. et al. PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development 122, 983–995 (1996)

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Hynes, M. & Rosenthal, A. Specification of dopaminergic and serotonergic neurons in the vertebrate CNS. Curr. Opin. Neurobiol. 9, 26–36 (1999)

    CAS  Article  Google Scholar 

  19. 19

    Wurst, W. & Bally-Cuif, L. Neural plate patterning: upstream and downstream of the isthmic organizer. Nature Rev. Neurosci. 2, 99–108 (2001)

    CAS  Article  Google Scholar 

  20. 20

    Ye, W., Shimamura, K., Rubenstein, J. L., Hynes, M. A. & Rosenthal, A. FGF and Shh signals control dopaminergic and serotonergic cell fate in the anterior neural plate. Cell 93, 755–766 (1998)

    CAS  Article  Google Scholar 

  21. 21

    Broccoli, V., Boncinelli, E. & Wurst, W. The caudal limit of Otx2 expression positions the isthmic organizer. Nature 401, 164–168 (1999)

    ADS  CAS  Article  Google Scholar 

  22. 22

    Joyner, A. L., Liu, A. & Millet, S. Otx2, Gbx2 and Fgf8 interact to position and maintain a mid-hindbrain organizer. Curr. Opin. Cell Biol. 12, 736–741 (2000)

    CAS  Article  Google Scholar 

  23. 23

    Tao, W. & Lai, E. Telencephalon-restricted expression of BF-1, a new member of the HNF-3/fork head gene family, in the developing rat brain. Neuron 8, 957–966 (1992)

    CAS  Article  Google Scholar 

  24. 24

    Wurst, W., Auerbach, A. B. & Joyner, A. L. Multiple developmental defects in Engrailed-1 mutant mice: an early mid-hindbrain deletion and patterning defects in forelimbs and sternum. Development 120, 2065–2075 (1994)

    CAS  Google Scholar 

  25. 25

    Smidt, M. P. et al. A second independent pathway for development of mesencephalic dopaminergic neurons requires Lmx1b. Nature Neurosci. 3, 337–341 (2000)

    CAS  Article  Google Scholar 

  26. 26

    Gerfen, C. R., Baimbridge, K. G. & Thibault, J. The neostriatal mosaic: III. Biochemical and developmental dissociation of patch-matrix mesostriatal systems. J. Neurosci. 7, 3935–3944 (1987)

    CAS  Article  Google Scholar 

  27. 27

    Reyport, S. et al. Identified postnatal mesolimbic dopamine neurons in culture; morphology and electrophysiology. J. Neurosci. 12, 4264–4280 (1992)

    Article  Google Scholar 

  28. 28

    Rohrbacher, J., Ichinohe, N. & Kitai, S. T. Electrophysiological characteristics of substantia nigra neurons in organotypic cultures: spontaneous and evoked activities. Neuroscience 97, 703–714 (2000)

    CAS  Article  Google Scholar 

  29. 29

    Fiorillo, C. D. & Williams, J. T. Glutamate mediates an inhibitory postsynaptic potential in dopamine neurons. Nature 394, 78–82 (1998)

    ADS  CAS  Article  Google Scholar 

  30. 30

    Abrous, D. N., Shaltot, A. R., Torres, E. M. & Dunnett, S. B. Dopamine-rich grafts in the neostriatum and/or nucleus accumbens: effects on drug-induced behaviours and skilled paw-reaching. Neuroscience 53, 187–197 (1993)

    CAS  Article  Google Scholar 

  31. 31

    Nikkhah, G., Duan, W. M., Knappe, U., Jödicke, A. & Björklund, A. Restoration of complex sensorimotor behaviour and skilled forelimb use by a modified nigral cell suspension transplantation approach in the rat Parkinson model. Neuroscience 56, 33–43 (1993)

    CAS  Article  Google Scholar 

  32. 32

    Zuddas, A., Corsini, G. U., Barker, J. L., Kopin, I. J. & di Porzio, U. Specific reinnervation of lesioned mouse striatum by grafted mesencephalic dopaminergic neurons. Eur. J. Neurosci. 3, 77–85 (1991)

    Article  Google Scholar 

  33. 33

    Hudson, J. L., Bickford, P., Johansson, M., Hoffer, B. J. & Stromberg, I. Target and neurotransmitter specificity of fetal central nervous system transplants: importance for functional reinnervation. J. Neurosci. 14, 283–290 (1994)

    CAS  Article  Google Scholar 

  34. 34

    Björklund, A. & Lindvall, O. Cell replacement therapies for central nervous system disorders. Nature Neurosci. 3, 537–544 (2000)

    Article  Google Scholar 

  35. 35

    Björklund, L. M. et al. Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Proc. Natl Acad. Sci. USA 99, 2344–2349 (2002)

    ADS  Article  Google Scholar 

  36. 36

    Gross, C. et al. Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult. Nature 416, 396–400 (2002)

    ADS  CAS  Article  Google Scholar 

  37. 37

    Sawa, A. & Snyder, S. H. Schizophrenia: diverse approaches to a complex disease. Science 296, 692–695 (2002)

    ADS  CAS  Article  Google Scholar 

  38. 38

    Mallamaci, A., Di Blas, E., Briata, P., Boncinelli, E. & Corte, G. OTX2 homeoprotein in the developing central nervous system and migratory cells of the olfactory area. Mech. Dev. 58, 165–178 (1996)

    CAS  Article  Google Scholar 

  39. 39

    Le, W. L., Conneely, O. M., He, Y., Jankovic, J. & Appel, S. H. Reduced Nurr1 expression increases the vulnerability of mesencephalic dopamine neurons to MPTP-induced injury. J. Neurochem. 73, 2218–2221 (1999)

    CAS  Google Scholar 

  40. 40

    Auerbach, J. M., Eiden, M. V. & McKay, R. D. Transplanted CNS stem cells form functional synapses in vivo. Eur. J. Neurosci. 12, 1696–1704 (2000)

    CAS  Article  Google Scholar 

  41. 41

    Olsson, M., Nikkhah, G., Bentlage, C. & Björklund, A. Forelimb akinesia in the rat Parkinson model: Differential effects of dopamine agonists and nigral transplants as assessed by a new stepping test. J. Neurosci. 15, 3863–3875 (1995)

    CAS  Article  Google Scholar 

  42. 42

    Montoya, C. P., Campbell, H. L., Pemberton, K. D. & Dunnett, S. B. The ‘staircase test’: a measure of independent forelimb reaching and grasping abilities in rats. J. Neurosci. Methods 36, 219–228 (1991)

    CAS  Article  Google Scholar 

  43. 43

    Schallert, T., Fleming, S. M., Leasure, J. L., Tillerson, J. L. & Bland, S. T. CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury. Neuropharmacology 39, 777–787 (2000)

    CAS  Article  Google Scholar 

Download references


We thank J. Harvey-White for technical assistance with HPLC, P. Brasted for advice on the non-pharmacological evaluation of the grafted animals, and J. Kordower for supplying boxes for the paw-reaching test, E. Lai for the anti-bB1 antibody and G. Corte for the anti-OTX2 antibody. We thank D. Owens for critical discussion of the manuscript. J.A.R.-G. was supported by a postdoctoral fellowship from the Spanish Ministerio de Educación, Cultura y Deporte. I.V. is a Pew Latin American fellow. We thank the National Parkinson Foundation and the Tuchman Foundation for their support.

Author information



Corresponding author

Correspondence to Ron McKay.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kim, JH., Auerbach, J., Rodríguez-Gómez, J. et al. Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease. Nature 418, 50–56 (2002).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing