Ephrin-A2 reverse signaling negatively regulates neural progenitor proliferation and neurogenesis

  1. Johan Holmberg1,
  2. Annika Armulik1,
  3. Kirsten-André Senti1,3,
  4. Karin Edoff1,
  5. Kirsty Spalding1,
  6. Stefan Momma1,
  7. Rob Cassidy1,
  8. John G. Flanagan2, and
  9. Jonas Frisén1,4
  1. 1Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institute, SE-171 77 Stockholm, Sweden; 2Department of Cell Biology and Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115, USA

Abstract

The number of cells in an organ is regulated by mitogens and trophic factors that impinge on intrinsic determinants of proliferation and apoptosis. We here report the identification of an additional mechanism to control cell number in the brain: EphA7 induces ephrin-A2 reverse signaling, which negatively regulates neural progenitor cell proliferation. Cells in the neural stem cell niche in the adult brain proliferate more and have a shorter cell cycle in mice lacking ephrin-A2. The increased progenitor proliferation is accompanied by a higher number of cells in the olfactory bulb. Disrupting the interaction between ephrin-A2 and EphA7 in the adult brain of wild-type mice disinhibits proliferation and results in increased neurogenesis. The identification of ephrin-A2 and EphA7 as negative regulators of progenitor cell proliferation reveals a novel mechanism to control cell numbers in the brain.

Keywords

Footnotes

  • Supplemental material is available at http://www.genesdev.org.

  • Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.326905.

  • 3 Present address: Department of Developmental Biology, Stockholm University, SE-10961 Stockholm, Sweden.

  • 4 Corresponding author.

    4 E-MAIL jonas.frisen{at}cmb.ki.se; FAX 46-8-324927.

    • Accepted December 16, 2004.
    • Received October 1, 2004.
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