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A TAG1-APP signalling pathway through Fe65 negatively modulates neurogenesis

Nature Cell Biology volume 10, pages 283–294 (2008)Cite this article

An Erratum to this article was published on 01 April 2008

Abstract

The release of amyloid precursor protein (APP) intracellular domain (AICD) may be triggered by extracellular cues through γ-secretase-dependent cleavage. AICD binds to Fe65, which may have a role in AICD-dependent signalling; however, the functional ligand has not been characterized. In this study, we have identified TAG1 as a functional ligand of APP. We found that, through an extracellular interaction with APP, TAG1 increased AICD release and triggered Fe65-dependent activity in a γ-secretase-dependent manner. TAG1, APP and Fe65 colocalized in the neural stem cell niche of the fetal ventricular zone. Neural precursor cells from TAG1−/−, APP−/− and TAG1−/−;APP−/− mice had aberrantly enhanced neurogenesis, which was significantly reversed in TAG1−/− mice by TAG1 or AICD but not by AICD mutated at the Fe65 binding site. Notably, TAG1 reduced normal neurogenesis in Fe65+/+ mice. Abnormally enhanced neurogenesis also occurred in Fe65−/− mice but could not be reversed by TAG1. These results describe a TAG1–APP signalling pathway that negatively modulates neurogenesis through Fe65.

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Figure 1: Cell adhesion assay showing that TAG1 is a binding partner of APP.
Figure 2: Expression of APP and TAG1 in the fetal neural stem cell niche and NPCs.
Figure 3: Neurogenesis in NPCs isolated from APP+/+ and APP−/− (a), TAG1+/+ and TAG1−/− (b), and TAG1+/+;APP+/+ and TAG1−/−;APP−/− double mutant (c) mice.
Figure 4: TAG1 triggers AICD release.
Figure 5: Neurogenesis in the NPCs of TAG1-deficient mice is reduced by treatment with either TAG1 or AICD.
Figure 6: Expression of Fe65 in the fetal neural stem cell niche and NPCs and downregulated neurogenesis in NPCs isolated from Fe65-knockout mice.
Figure 7: TAG1–APP signalling pathway through Fe65 modulates neurogenesis.

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Acknowledgements

We thank D. J. Selkoe for providing APP antibodies, T. Sudhof for the APPGal4, APP*–Gal4 and Fe65–Gal plasmids, S. Sisodia for mouse APP 695 cDNA, C. Schmidt for APP–Fc, and Q. D. Hu, X. Y. Cui, J. L. Hu, F. C. K. Tan and S. Hébert for technical assistance. This work was supported by grants to Z. C. Xiao from the National Medical Research Council of Singapore, Singapore Health Services, Department of Clinical Research, Singapore General Hospital, Institute of Molecular and Cell Biology, A*STAR, Singapore, and a grant to both Z. C. Xiao and D. Bagnard from MERLION, a Singapore-France joint scientific programme. M. Schachner is New Jersey Professor for Spinal Cord Research

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Author notes

  1. Toshitaka Futagawa and Wu-Lin Yang: These authors contributed equally to the work.

Authors and Affiliations

  1. Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, 138673, Singapore

    Quan-Hong Ma, Li Zeng & Zhi-Cheng Xiao

  2. Department of Clinical Research, Singapore General Hospital, 169608, Singapore

    Quan-Hong Ma, Toshitaka Futagawa, Wu-Lin Yang & Zhi-Cheng Xiao

  3. Zentrum fur Molekulare Neurobiologie, University of Hamburg, Hamburg, D-20251, Germany

    Quan-Hong Ma & Melitta Schachner

  4. INSERM U575, Physiopathologie du Systeme Nerveux, Centre de Neurochimie, Strasbourg, 67084, France

    Quan-Hong Ma & Dominique Bagnard

  5. Department of Clinical Pharmacy and Pharmacology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, 890-8520, Japan

    Toshitaka Futagawa & Yasuo Takeda

  6. Neuromedical Institute, Zhujiang Hospital of Southern Medical University, Guangzhou, 510282, China

    Xiao-Dan Jiang & Ru-Xiang Xu

  7. Keck Center for Collaborative Neuroscience, Rutgers University, Piscataway, 08854-6999, NJ, USA

    Melitta Schachner

  8. Centre for Developmental Genetics, School of Medicine and Biomedical Science, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK

    Andrew J. Furley

  9. Institute of Molecular Biology and Biotechnology and University of Crete Medical School, Heraklion, 71110, Crete, Greece

    Domna Karagogeos

  10. Department of Bioengineering, Nagaoka University of Technology, Nagaoka, 940-2188, Japan

    Kazutada Watanabe

  11. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore

    Gavin S. Dawe

  12. Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore

    Zhi-Cheng Xiao

Authors
  1. Quan-Hong Ma
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  14. Zhi-Cheng Xiao
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Contributions

Q.-H. M, T. F., W.-L. Y. and L. Z. performed the experiments and analysed the data (the contribution of Q.-H. M. to the experimental work was greatest, whereas that of T. F., W.-L. Y. were equivalent); X.-D. J., Y. T., R.-X. X., D. B., M. S., A. J. F., D. K. and K. W. provided materials and input to the experimental design; G. S. D. and Z.-C. X. planned and directed the project, designed the experiments and wrote the manuscript.

Corresponding authors

Correspondence to Gavin S. Dawe or Zhi-Cheng Xiao.

Supplementary information

Supplementary Information

Supplementary figures S1, S2, S3, S4, S5, S6 and Supplementary Experimental Procedures (PDF 556 kb)

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Ma, QH., Futagawa, T., Yang, WL. et al. A TAG1-APP signalling pathway through Fe65 negatively modulates neurogenesis. Nat Cell Biol 10, 283–294 (2008). https://doi.org/10.1038/ncb1690

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