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.
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Acknowledgements
We thank D. Hayward, S. Itohara, R. Kageyama, M. Nakafuku, E. Nishi, J. Nye, M. Okabe, H. Okano, A. Sehara-Fujisawa, G. Weinmaster, Z. Werb, S. Yamada and A. Zolkiewska for providing materials, R. Bronson for help on pathological examination, C. Blobel, E. Nishi, H. Sato, A. Shamma and T. Sunabori for discussions, A. Sehara-Fujisawa for critical reading of the manuscript, M. Ewen for encouragement, H. Gu, T. Kawai, B.P.K. Mallawaarachchi and A. Nishimoto for technical assistance and A. Miyazaki for secretarial assistance. This work was supported by funds from The 21st Century COE Formation, Public Trust Haraguchi Memorial Cancer Research Fund, Mitsubishi Pharma Research Foundation, Research Grant of the Princess Takamatsu Cancer Research Fund (05-23706) and Japan Ministry of Education, Culture, Sports, Science and Technology. T. Muraguchi would like to thank Japan Student Services Organization and The Naito Foundation for support.
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C.T. conceived the project. C.T. and T. Muraguchi designed the experiments. T. Muraguchi generated most of the data. Y.T. purified proteins and performed kinetic assays. T.O. performed in utero electroporation, which T. Muraguchi analyzed. S.K. provided Supplementary Figure 5c. A.L. provided synthetic metalloprotease inhibitors. C.T. wrote most of the manuscript. All authors substantially contributed to this work.
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Supplementary information
Supplementary Fig. 1
The neural phenotype in Reck;Mmp-2;Mmp-9 triple knockout mice. (PDF 6585 kb)
Supplementary Fig. 2
BrdU incorporation to NPCs analyzed in Figure 4. (PDF 789 kb)
Supplementary Fig. 3
Assessment of the off-target effects of shRNAs used for analyses in Figure 4. (PDF 1012 kb)
Supplementary Fig. 4
Assessment of the off-target effects of shRNAs used for analyses in Figure 5. (PDF 1056 kb)
Supplementary Fig. 5
The specificity of RECK activity on ADAMs. (PDF 722 kb)
Supplementary Fig. 6
Effects of membrane-unanchored RECK on ADAM10-dependent Delta shedding. (PDF 513 kb)
Supplementary Fig. 7
Effects of RECK on Notch shedding. (PDF 498 kb)
Supplementary Fig. 8
Cell autonomous effects of RECK on the intercellular Notch signaling. (PDF 524 kb)
Supplementary Table 1
Sequence of primers used in RT-PCR. (PDF 30 kb)
Supplementary Table 2
DNA sequences used as the shRNA template. (PDF 33 kb)
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Muraguchi, T., Takegami, Y., Ohtsuka, T. et al. RECK modulates Notch signaling during cortical neurogenesis by regulating ADAM10 activity. Nat Neurosci 10, 838–845 (2007). https://doi.org/10.1038/nn1922
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DOI: https://doi.org/10.1038/nn1922
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