A TAG1-APP signalling pathway through Fe65 negatively modulates neurogenesis

Quan-Hong Ma, Toshitaka Futagawa, Wu-Lin Yang, Xiao-Dan Jiang, Li Zeng, Yasuo Takeda, Ru-Xiang Xu, Dominique Bagnard, Melitta Schachner, Andrew J Furley, Domna Karagogeos, Kazutada Watanabe, Gavin S Dawe, Zhi-Cheng Xiao

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147 Citations (Scopus)

Abstract

The release of amyloid precursor protein (APP) intracellular domain (AICD) may be triggered by extracellular cues through gamma-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 gamma-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.
Original languageEnglish
Pages (from-to)283 - 294
Number of pages12
JournalNature Cell Biology
Volume10
Issue number3
DOIs
Publication statusPublished - 2008
Externally publishedYes

Cite this

Ma, Q-H., Futagawa, T., Yang, W-L., Jiang, X-D., Zeng, L., Takeda, Y., Xu, R-X., Bagnard, D., Schachner, M., Furley, A. J., Karagogeos, D., Watanabe, K., Dawe, G. S., & Xiao, Z-C. (2008). A TAG1-APP signalling pathway through Fe65 negatively modulates neurogenesis. Nature Cell Biology, 10(3), 283 - 294. https://doi.org/10.1038/ncb1690