Article abstract
Nature Neuroscience 10, 838 - 845 (2007)
Published online: 10 June 2007 | doi:10.1038/nn1922
RECK modulates Notch signaling during cortical neurogenesis by regulating ADAM10 activity
Teruyuki Muraguchi1,7, Yujiro Takegami1, Toshiyuki Ohtsuka2, Shunsuke Kitajima1, Ediriweera P S Chandana1, Akira Omura1, Takao Miki1,3, Rei Takahashi4, Naoya Matsumoto5, Andreas Ludwig6, Makoto Noda1 & Chiaki Takahashi1,3
Abstract
We report that during cortical development in the mouse embryo, reversion-inducing cysteine-rich protein with Kazal motifs (RECK) critically regulates Notch signaling by antagonizing the ectodomain shedding of Notch ligands, which is mediated by a disintegrin and metalloproteinase domain 10 (ADAM10). In the embryonic brain, RECK is specifically expressed in Nestin-positive neural precursor cells (NPCs). Reck-deficient NPCs undergo precocious differentiation that is associated with downregulated Nestin expression, impaired Notch signaling and defective self-renewal. These phenotypes were substantially rescued either by enhancing Notch signaling or by suppressing endogenous ADAM10 activity. Consequently, we found that RECK regulates the ectodomain shedding of Notch ligands by directly inhibiting the proteolytic activity of ADAM10. This mechanism appeared to be essential for Notch ligands to properly induce Notch signaling in neighboring cells. These findings indicate that RECK is a physiological inhibitor of ADAM10, an upstream regulator of Notch signaling and a critical modulator of brain development.
- Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
- Institute for Virus Research, Kyoto University, Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
- The 21st Century Center of Excellence (COE) Formation, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
- Department of Pathology and Tumor Biology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
- Department of Anatomy and Neurobiology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Pauwelsstrasse 30, Aachen D-52074, Germany.
- Present address: Division of Molecular Genetics, Center for Cancer and Stem Cell Research, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-0934, Japan.
Correspondence to: Chiaki Takahashi1,3 e-mail: chtakaha@virus.kyoto-u.ac.jp
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