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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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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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.
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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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DOI: https://doi.org/10.1038/ncb1690
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