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A TAG1-APP signalling pathway through Fe65 negatively modulates neurogenesis

Nature Cell Biology volume 10, pages 283294 (2008) | Download Citation


  • An Erratum to this article was published on 01 April 2008


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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  1. 1.

    & Presenilin diversifies its portfolio. Trends Genet. 23, 140–150 (2007).

  2. 2.

    Neural GPI-anchored cell adhesion molecules. Front. Biosci. 8, s1304–s1320 (2003).

  3. 3.

    et al. NB-3/Notch1 pathway via Deltex1 promotes neural progenitor cell differentiation into oligodendrocytes. J. Biol. Chem. 279, 25858–25865 (2004).

  4. 4.

    et al. F3 acts as a functional ligand for Notch during oligodendrocyte maturation. Cell 115, 163–175 (2003).

  5. 5.

    & Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration. Annu. Rev. Neurosci. 26, 565–597 (2003).

  6. 6.

    et al. TAG1-deficient mice have marked elevation of adenosine A1 receptors in the hippocampus. Biochem. Biophys. Res. Commun. 281, 220–226 (2001).

  7. 7.

    & A transcriptively active complex of APP with Fe65 and histone acetyltransferase Tip60. Science 293, 115–120 (2001).

  8. 8.

    & Adaptor protein interactions: modulators of amyloid precursor protein metabolism and Alzheimer's disease risk? Exp. Neurol. 185, 208–219 (2004).

  9. 9.

    et al. Generation of the β-amyloid peptide and the amyloid precursor protein C-terminal fragment gamma are potentiated by FE65L1. J. Biol. Chem. 278, 51100–51107 (2003).

  10. 10.

    & Characterization of an amyloid precursor protein-binding protein Fe65L2 and its novel isoforms lacking phosphotyrosine-interaction domains. Biochem. J. 367, 687–695 (2002).

  11. 11.

    Correlations between prenatally-induced alterations in CNS cell populations and postnatal function. Teratology 16, 235–246 (1977).

  12. 12.

    & Dissection of amyloid-β precursor protein-dependent transcriptional transactivation. J. Biol. Chem. 279, 24601–24611 (2004).

  13. 13.

    et al. Association of TAG1 with Caspr2 is essential for the molecular organization of juxtaparanodal regions of myelinated fibers. J. Cell Biol. 162, 1161–1172 (2003).

  14. 14.

    , , & Prevention of neuronal cell death by neural adhesion molecules L1 and CHL1. J. Neurobiol. 38, 428–439 (1999).

  15. 15.

    , , & High-copy expression vector based on amplification-promoting sequences. DNA Cell Biol. 13, 437–445 (1994).

  16. 16.

    et al. β-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity. Cell 81, 525–531 (1995).

  17. 17.

    et al. Isoform-specific knockout of FE65 leads to impaired learning and memory. J. Neurosci. Res. 75, 12–24 (2004).

  18. 18.

    , , , & Phosphorylation-dependent regulation of the interaction of amyloid precursor protein with Fe65 affects the production of beta-amyloid. J. Biol. Chem. 276, 40353–40361 (2001).

  19. 19.

    et al. Regulated intramembrane proteolysis of amyloid precursor protein and regulation of expression of putative target genes. EMBO Rep. 7, 739–745 (2006).

  20. 20.

    et al. Alkalizing drugs induce accumulation of amyloid precursor protein by-products in luminal vesicles of multivesicular bodies. J. Biol. Chem. 282, 18197–18205 (2007).

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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

Author information

Author notes

    • Toshitaka Futagawa
    •  & Wu-Lin Yang

    These authors contributed equally to the work.


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

    • Quan-Hong Ma
    • , Li Zeng
    •  & Zhi-Cheng Xiao
  2. Department of Clinical Research, Singapore General Hospital, Singapore 169608.

    • Quan-Hong Ma
    • , Toshitaka Futagawa
    • , Wu-Lin Yang
    •  & Zhi-Cheng Xiao
  3. Zentrum fur Molekulare Neurobiologie, University of Hamburg, D-20251 Hamburg, Germany.

    • Quan-Hong Ma
    •  & Melitta Schachner
  4. INSERM U575, Physiopathologie du Systeme Nerveux, Centre de Neurochimie, 67084 Strasbourg, 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, NJ 08854-6999, 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, Singapore 117597.

    • Gavin S. Dawe
  12. Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.

    • Zhi-Cheng Xiao


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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.

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    Supplementary Information

    Supplementary figures S1, S2, S3, S4, S5, S6 and Supplementary Experimental Procedures

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