Article | Published:

Glial cells generate neurons: the role of the transcription factor Pax6

Nature Neuroscience volume 5, pages 308315 (2002) | Download Citation

Subjects

  • A Corrigendum to this article was published on 01 May 2002

Abstract

Radial glial cells, ubiquitous throughout the developing CNS, guide radially migrating neurons and are the precursors of astrocytes. Recent evidence indicates that radial glial cells also generate neurons in the developing cerebral cortex. Here we investigated the role of the transcription factor Pax6 expressed in cortical radial glia. We showed that radial glial cells isolated from the cortex of Pax6 mutant mice have a reduced neurogenic potential, whereas the neurogenic potential of non-radial glial precursors is not affected. Consistent with defects in only one neurogenic lineage, the number of neurons in the Pax6 mutant cortex in vivo is reduced by half. Conversely, retrovirally mediated Pax6 expression instructs neurogenesis even in astrocytes from postnatal cortex in vitro. These results demonstrated an important role of Pax6 as intrinsic fate determinant of the neurogenic potential of glial cells.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    The neural crest cell lineage problem: neuropoiesis? Neuron 3, 1–12 (1989).

  2. 2.

    Neural development: instructions for neural diversity. Curr. Biol. 7, R168–R171 (1997).

  3. 3.

    & Evidence for multiple precursor cell types in the embryonic rat cerebral cortex. Neuron 14, 1181–1188 (1995).

  4. 4.

    et al. Multiple restricted lineages in the embryonic rat cerebral cortex. Development 117, 553–561 (1993).

  5. 5.

    , & Systematic widespread clonal organization in cerebral cortex. Neuron 15, 299–310 (1995).

  6. 6.

    et al. Timing of CNS cell generation: a programmed sequence of neuron and glial cell production from isolated murine cortical stem cells. Neuron 28, 69–80 (2000).

  7. 7.

    , & Cell lineage in the cerebral cortex of the mouse studied in vivo and in vitro with a recombinant retrovirus. Neuron 1, 635–647 (1988).

  8. 8.

    , , , & Intrinsic programs of patterned cell lineages in isolated vertebrate CNS ventricular zone cells. Development 125, 3143–3152 (1998).

  9. 9.

    & Pax-6, a murine paired box gene, is expressed in the developing CNS. Development 113, 1435–1449 (1991).

  10. 10.

    , & Pax6 controls radial glia differentiation in the cerebral cortex. Neuron 21, 1031–1044 (1998).

  11. 11.

    , , & Pax6 modulates the dorsoventral patterning of the mammalian telencephalon. J. Neurosci. 20, 8042–8050 (2000).

  12. 12.

    , , & Pax6-dependent regulation of adhesive patterning, R-cadherin expression and boundary formation in developing forebrain. Development 124, 3765–3777 (1997).

  13. 13.

    , & Isolation of radial glial cells by fluorescent-activated cell sorting reveals a neuronal lineage. Development 127, 5253–5263 (2000).

  14. 14.

    , , , & Neurons derived from radial glial cells establish radial units in neocortex. Nature 409, 714–720 (2001).

  15. 15.

    , , & Asymmetric inheritance of radial glial fibers by cortical neurons. Neuron 31, 727–741 (2001).

  16. 16.

    et al. Generation of regionally specified neurons in expanded glial cultures derived from the mouse and human lateral ganglionic eminence. Mol. Cell Neurosci. 17, 811–820 (2001).

  17. 17.

    et al. Live astrocytes visualized by green fluorescent protein in transgenic mice. Dev. Biol. 187, 36–42 (1997).

  18. 18.

    et al. Mouse Small eye results from mutations in a paired-like homeobox-containing gene. Nature 354, 522–525 (1991).

  19. 19.

    , , & Defects of neuronal migration and the pathogenesis of cortical malformations are associated with Small eye (Sey) in the mouse, a point mutation at the Pax-6 locus. Acta Neuropathol. (Berl.) 86, 126–135 (1993).

  20. 20.

    , , , & Determination of the migratory capacity of embryonic cortical cells lacking the transcription factor Pax-6. Development 124, 5087–5096 (1997).

  21. 21.

    , & The role of Pax6 in restricting cell migration between developing cortex and basal ganglia. Development 126, 5569–5579 (1999).

  22. 22.

    , & Neurotrophins are required for nerve growth during development. Nat. Neurosci. 4, 29–37 (2001).

  23. 23.

    et al. Emx2 promotes symmetric cell divisions and a multipotential fate in precursors from the cerebral cortex. Mol. Cell Neurosci. 18, 485–582 (2001).

  24. 24.

    , & Evidence that retroviruses integrate into post-replication host DNA. EMBO J. 12, 4969–4974 (1993).

  25. 25.

    , , & Forebrain patterning defects in Small eye mutant mice. Development 122, 3453–3465 (1996).

  26. 26.

    , & Neurons are generated in confluent astroglial cultures of rat neonatal neocortex. Neuroscience 78, 957–966 (1997).

  27. 27.

    , , , & Identification of a multipotent astrocytic stem cell in the immature and adult mouse brain. Proc. Natl. Acad. Sci. USA 97, 13883–13888 (2000).

  28. 28.

    , , , & Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97, 703–716 (1999).

  29. 29.

    , & NeuN, a neuronal specific nuclear protein in vertebrates. Development 116, 201–211 (1992).

  30. 30.

    , , & Neural bHLH genes control the neuronal versus glial fate decision in cortical progenitors. Neuron 29, 401–413 (2001).

  31. 31.

    et al. Neurogenin promotes neurogenesis and inhibits glial differentiation by independent mechanisms. Cell 104, 365–376 (2001).

  32. 32.

    , & Genetic control of dorsal–ventral identity in the telencephalon: opposing roles for Pax6 and Gsh2. Development 127, 4361–4371 (2000).

  33. 33.

    et al. Dynamic expression of basic helix-loop-helix Olig family members: implication of Olig2 in neuron and oligodendrocyte differentiation and identification of a new member, Olig3. Mech. Dev. 99, 143–148 (2000).

  34. 34.

    , , & Characterization of CNS precursor subtypes and radial glia. Dev. Biol. 229, 15–30 (2001).

  35. 35.

    , , & Cortical upper layer neurons derive from the subventricular zone as indicated by Svet1 gene expression. Development 128, 1983–1993 (2001).

  36. 36.

    , , , & Pax6 is required to regulate the cell cycle and the rate of progression from symmetrical to asymmetrical division in mammalian cortical progenitors. Development 129, 455–466 (2002).

  37. 37.

    et al. Generation of neurons by transient expression of neural bHLH proteins in mammalian cells. Development 127, 693–702 (2000).

  38. 38.

    et al. Pax6 is required for the multipotent state of retinal progenitor cells. Cell 105, 43–55 (2001).

  39. 39.

    , , & Crossregulation between Neurogenin2 and pathways specifying neuronal identity in the spinal cord. Neuron 31, 203–217 (2001).

  40. 40.

    et al. A role for neural determination genes in specifying the dorsoventral identity of telencephalic neurons. Genes Dev. 14, 67–80 (2000).

  41. 41.

    How are neurons specified: master or positional control? Trends Neurosci. 21, 135–136 (1998).

  42. 42.

    , , & Astrocytes give rise to new neurons in the adult mammalian hippocampus. J. Neurosci. 21, 7153–7160 (2001).

  43. 43.

    , & The encephalomyocarditis virus internal ribosome entry site allows efficient coexpression of two genes from a recombinant provirus in cultured cells and in embryos. Mol. Cell Biol. 11, 5848–5859 (1991).

  44. 44.

    , , & Production of high-titer helper-free retroviruses by transient transfection. Proc. Natl. Acad. Sci. USA 90, 8392–8396 (1993).

  45. 45.

    , & The generation of neurons and oligodendrocytes from a common precursor cell. Neuron 7, 685–693 (1991).

  46. 46.

    et al. Crossinhibitory activities of Ngn1 and Math1 allow specification of distinct dorsal interneurons. Neuron 31, 219–232 (2001).

  47. 47.

    et al. Combinatorial roles of Olig2 and Neurogenin2 in the coordinated induction of pan-neuronal and subtype-specific properties of motoneurons. Neuron 31, 757–771 (2001).

  48. 48.

    , & MASH1 activates expression of the paired homeodomain transcription factor Phox2a, and couples pan-neuronal and subtype-specific components of autonomic neuronal identity. Development 125, 609–620 (1998).

Download references

Acknowledgements

We are grateful to A. Stoykova and A. Messing for the Sey- and 94-4 mice, respectively; D. Anderson, F. Guillemot, C. Lagenaur, P. Leprince and J. Price for antisera; J.E. Majors for the viral backbone plasmid; H. Wekerle and W. Klinkert for access to the FACSort; M. Öcalan for expertise in tissue culture; and F. Guillemot, B. Grothe, M. Korte and R. Klein for comments on the manuscript. The monoclonal antibody against nestin was obtained from the Developmental Studies Hybridoma Bank. Our work was supported by the EU Grant QLK3-1999-00894, European Cell Therapy in the Nervous System, a Marie Curie Fellowship to P.M. and the Max-Planck Society. F.C. is an Assistant Telethon Scientist (grant 38/CP).

Author information

Author notes

    • Nico Heins
    •  & Paolo Malatesta

    P.M. and N.H. contributed equally to this work

Affiliations

  1. Max-Planck Institute of Neurobiology, Am Klopferspitz 18a, 82152, Planegg-Martinsreid, Munich, Germany

    • Nico Heins
    • , Paolo Malatesta
    • , Michael A. Hack
    • , Prisca Chapouton
    •  & Magdalena Götz
  2. Dipartimento di Biologia, Universita degli studi 'Tor Vergata', Via della Ricerca Scientifica, 00133 Rome, Italy

    • Francesco Cecconi
    •  & Yves-Alain Barde
  3. University of Tokyo, Graduate School of Medicine, 7-3-1 Hongo, Bunkyoku, Tokyo, 113-0033 Japan

    • Masato Nakafuku
  4. Friedrich Miescher Institute for Biomedical Research, Maulsbeerstr. 66, 4058 Basel, Switzerland

    • Kerry Lee Tucker

Authors

  1. Search for Nico Heins in:

  2. Search for Paolo Malatesta in:

  3. Search for Francesco Cecconi in:

  4. Search for Masato Nakafuku in:

  5. Search for Kerry Lee Tucker in:

  6. Search for Michael A. Hack in:

  7. Search for Prisca Chapouton in:

  8. Search for Yves-Alain Barde in:

  9. Search for Magdalena Götz in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Magdalena Götz.

Supplementary information

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nn828

Further reading