Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells

  1. Seiji Hitoshi1,6,9,
  2. Tania Alexson1,
  3. Vincent Tropepe1,7,
  4. Dorit Donoviel2,8,
  5. Andrew J. Elia3,
  6. Jeffrey S. Nye4,
  7. Ronald A. Conlon5,
  8. Tak W. Mak3,
  9. Alan Bernstein2, and
  10. Derek van der Kooy1,9
  1. 1Department of Anatomy and Cell Biology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; 2Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada; 3The Amgen Institute, Ontario Cancer Institute, and Departments of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario M5G 2C1, Canada; 4Molecular Pharmacology and Biological Chemistry and Pediatrics, Northwestern University Medical School, Chicago, Illinois 60611, USA; 5Department of Genetics, Case Western Reserve University, Cleveland, Ohio 44106, USA

Abstract

Neural stem cells, which exhibit self-renewal and multipotentiality, are generated in early embryonic brains and maintained throughout the lifespan. The mechanisms of their generation and maintenance are largely unknown. Here, we show that neural stem cells are generated independent of RBP-Jκ, a key molecule in Notch signaling, by using RBP-Jκ−/− embryonic stem cells in an embryonic stem cell-derived neurosphere assay. However, Notch pathway molecules are essential for the maintenance of neural stem cells; they are depleted in the early embryonic brains ofRBP-Jκ−/− or Notch1 −/− mice. Neural stem cells also are depleted in embryonic brains deficient for the presenilin1 (PS1) gene, a key regulator in Notch signaling, and are reduced in PS1 +/− adult brains. Both neuronal and glial differentiation in vitro were enhanced by attenuation of Notch signaling and suppressed by expressing an active form of Notch1. These data are consistent with a role for Notch signaling in the maintenance of the neural stem cell, and inconsistent with a role in a neuronal/glial fate switch.

Keywords

Footnotes

  • Present addresses: 6Department of Neurology, University of Tokyo, Tokyo 113-8655, Japan; 7Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; 8Lexicon Genetics, Inc., The Woodlands, TX 77381, USA.

  • 9 Corresponding authors.

  • E-MAIL shitoshi-tky{at}umin.ac.jp; FAX 81-3-5800-6548.

  • E-MAIL derek.van.der.kooy{at}utoronto.ca; FAX (416) 978-3844.

  • Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.975202.

    • Received August 31, 2001.
    • Accepted February 11, 2002.
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