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Expression and function of orphan nuclear receptor TLX in adult neural stem cells

Nature volume 427, pages 78–83 (2004)Cite this article

Abstract

The finding of neurogenesis in the adult brain led to the discovery of adult neural stem cells1. TLX was initially identified as an orphan nuclear receptor expressed in vertebrate forebrains2 and is highly expressed in the adult brain3. The brains of TLX-null mice have been reported to have no obvious defects during embryogenesis4; however, mature mice suffer from retinopathies5, severe limbic defects, aggressiveness, reduced copulation and progressively violent behaviour4,6. Here we show that TLX maintains adult neural stem cells in an undifferentiated, proliferative state. We show that TLX-expressing cells isolated by fluorescence-activated cell sorting (FACS) from adult brains can proliferate, self-renew and differentiate into all neural cell types in vitro. By contrast, TLX-null cells isolated from adult mutant brains fail to proliferate. Reintroducing TLX into FACS-sorted TLX-null cells rescues their ability to proliferate and to self-renew. In vivo, TLX mutant mice show a loss of cell proliferation and reduced labelling of nestin in neurogenic areas in the adult brain. TLX can silence glia-specific expression of the astrocyte marker GFAP in neural stem cells, suggesting that transcriptional repression may be crucial in maintaining the undifferentiated state of these cells.

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Figure 1: Expression of TLX in adult NSCs.
Figure 2: TLX-positive cells are self-renewable and multipotent.
Figure 3: TLX is a transcriptional repressor.
Figure 4: Loss of nestin and BrdU staining in TLX mutant mouse brain.

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References

  1. Gage, F. H. Mammalian neural stem cells. Science 287, 1433–1438 (2000)

    Article  ADS  CAS  Google Scholar 

  2. Yu, R. T., McKeown, M., Evans, R. M. & Umesono, K. Relationship between Drosophila gap gene tailless and a vertebrate nuclear receptor Tlx. Nature 370, 375–379 (1994)

    Article  ADS  CAS  Google Scholar 

  3. Monaghan, A. P., Grau, E., Bock, D. & Schutz, G. The mouse homolog of the orphan nuclear receptor tailless is expressed in the developing forebrain. Development 121, 839–853 (1995)

    CAS  PubMed  Google Scholar 

  4. Monaghan, A. P. et al. Defective limbic system in mice lacking the tailless gene. Nature 390, 515–517 (1997)

    Article  ADS  CAS  Google Scholar 

  5. Yu, R. T. et al. The orphan nuclear receptor Tlx regulates Pax2 and is essential for vision. Proc. Natl Acad. Sci. USA 97, 2621–2625 (2000)

    Article  ADS  CAS  Google Scholar 

  6. Chiang, M. Y. & Evans, R. M. Reverse Genetic Analysis of Nuclear Receptors, RXRg, RARb, and TLX in Mice (Dissertation, Univ. California, San Diego, 1997)

    Google Scholar 

  7. Gage, F. H. Neurogenesis in the adult brain. J. Neurosci. 22, 612–613 (2002)

    Article  CAS  Google Scholar 

  8. Lendahl, U., Zimmerman, L. B. & McKay, R. D. CNS stem cells express a new class of intermediate filament protein. Cell 60, 585–595 (1990)

    Article  CAS  Google Scholar 

  9. Reynolds, B. A., Tetzlaff, W. & Weiss, S. A multipotent EGF-responsive striatal embryonic progenitor cell produces neurons and astrocytes. J. Neurosci. 12, 4565–4574 (1992)

    Article  CAS  Google Scholar 

  10. Doetsch, F., Petreanu, L., Caille, I., Garcia-Verdugo, J. M. & Alvarez-Buylla, A. EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells. Neuron 36, 1021–1034 (2002)

    Article  CAS  Google Scholar 

  11. Allen, D. M. et al. Ataxia telangiectasia mutated is essential during adult neurogenesis. Genes Dev. 15, 554–566 (2001)

    Article  CAS  Google Scholar 

  12. Taupin, P. et al. FGF-2-responsive neural stem cell proliferation requires CCg, a novel autocrine/paracrine cofactor. Neuron 28, 385–397 (2000)

    Article  CAS  Google Scholar 

  13. Nakashima, K. et al. Synergistic signaling in fetal brain by STAT3–Smad1 complex bridged by p300. Science 284, 479–482 (1999)

    Article  ADS  CAS  Google Scholar 

  14. Lie, D. C. et al. The adult substantia nigra contains progenitor cells with neurogenic potential. J. Neurosci. 22, 6639–6649 (2002)

    Article  CAS  Google Scholar 

  15. Palmer, T. D., Markakis, E. A., Willhoite, A. R., Safar, F. & Gage, F. H. Fibroblast growth factor-2 activates a latent neurogenic program in neural stem cells from diverse regions of the adult CNS. J. Neurosci. 19, 8487–8497 (1999)

    Article  CAS  Google Scholar 

  16. Shi, Y. et al. Sharp, an inducible cofactor that integrates nuclear receptor repression and activation. Genes Dev. 15, 1140–1151 (2001)

    Article  CAS  Google Scholar 

  17. Misawa, K. et al. A method to identify cDNAs based on localization of green fluorescent protein fusion products. Proc. Natl Acad. Sci. USA 97, 3062–3066 (2000)

    Article  ADS  CAS  Google Scholar 

  18. Morita, S., Kojima, T. & Kitamura, T. Plat-E: an efficient and stable system for transient packaging of retroviruses. Gene Ther. 7, 1063–1066 (2000)

    Article  CAS  Google Scholar 

  19. Miyoshi, H., Blomer, U., Takahashi, M., Gage, F. H. & Verma, I. M. Development of a self-inactivating lentivirus vector. J. Virol. 72, 8150–8157 (1998)

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank G. Cabrera, S. Tiep, M. Nelson, H. Juguilon, J. Havstad, B. Miller, R. Summers, A. Consiglio, A. Huynh, L. Moore, A. Dearie and H. Lansford for technical help; M. L. Gage for editing; E. Stevens and E. Ong for administrative assistance; C. Zhang for comments on the manuscript; R. Marr and I. Verma for the lentiviral vector; and T. Kitamura for the pMY vector and PlatE cells. Y.S. is a fellow of the Susan G. Komen Breast Cancer Foundation. D.C.L. was supported by the Deutsche Forschungsgemeinschaft. P.T. was supported by the Pasarow Foundation. K.N. was supported by a Japan Society for the Promotion of Science (JSPS) Postdoctoral Fellowship for Research Abroad. R.M.E. is an Investigator of the Howard Hughes Medical Institute at the Salk Institute and March of Dimes Chair in Molecular and Developmental Biology. F.H.G. is the Adler Professor of Age-Related Neurodegenerative Diseases. This work was supported by the Howard Hughes Medical Institute, the NIH, the Christopher Reeve Paralysis Foundation, the National Institutes of Aging, the Michael J. Fox Foundation, Project ALS and the Lookout Fund.

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Authors and Affiliations

  1. Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California, 92037, USA

    Yanhong Shi, Ruth T. Yu & Ronald M. Evans

  2. Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California, 92037, USA

    D. Chichung Lie, Philippe Taupin, Kinichi Nakashima, Jasodhara Ray & Fred H. Gage

  3. Howard Hughes Medical Institute, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California, 92037, USA

    Ronald M. Evans

  4. Department of Cell Fate Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1, Honjo, Kumamoto, 860-0811, Japan

    Kinichi Nakashima

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Correspondence to Fred H. Gage or Ronald M. Evans.

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Supplementary information

Supplementary Figure 1: TLX-/- cells cultured in growth media at day 1 and 10. (JPG 30 kb)

41586_2004_BFnature02211_MOESM2_ESM.jpg

Supplementary Figure 2: Quantitation of nestin+ (a) and GFAP+ cells (b) from TLX+/- and TLX-/- culture in growth media. (JPG 41 kb)

Supplementary Figure 3: GFP fluorescence and nestin-staining of TLX-/- cells expressing TLX-GFP. (JPG 43 kb)

41586_2004_BFnature02211_MOESM4_ESM.jpg

Supplementary Figure 4: Quantitation of Ki67+ (a) and GFAP+ cells (b) in TLX-/- cells infected with control or TLX-GFP lentivirus. (JPG 42 kb)

Supplementary Figure Legends (DOC 23 kb)

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Shi, Y., Chichung Lie, D., Taupin, P. et al. Expression and function of orphan nuclear receptor TLX in adult neural stem cells. Nature 427, 78–83 (2004). https://doi.org/10.1038/nature02211

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