Article abstract
Nature Cell Biology 10, 283 - 294 (2008)
Published online: 17 February 2008 | doi:10.1038/ncb1690
There is an Erratum (April 2008) associated with this Article.
A TAG1-APP signalling pathway through Fe65 negatively modulates neurogenesis
Quan-Hong Ma1,2,3,4, Toshitaka Futagawa2,5,13, Wu-Lin Yang2,13, Xiao-Dan Jiang6, Li Zeng1, Yasuo Takeda5, Ru-Xiang Xu6, Dominique Bagnard4, Melitta Schachner3,7, Andrew J. Furley8, Domna Karagogeos9, Kazutada Watanabe10, Gavin S. Dawe11 & Zhi-Cheng Xiao1,2,12
Abstract
The release of amyloid precursor protein (APP) intracellular domain (AICD) may be triggered by extracellular cues through 
-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 -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.
- Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673.
- Department of Clinical Research, Singapore General Hospital, Singapore 169608.
- Zentrum fur Molekulare Neurobiologie, University of Hamburg, D-20251 Hamburg, Germany.
- INSERM U575, Physiopathologie du Systeme Nerveux, Centre de Neurochimie, 67084 Strasbourg, France.
- Department of Clinical Pharmacy and Pharmacology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8520, Japan.
- Neuromedical Institute, Zhujiang Hospital of Southern Medical University, Guangzhou, 510282, China.
- Keck Center for Collaborative Neuroscience, Rutgers University, Piscataway, NJ 08854-6999, USA.
- Centre for Developmental Genetics, School of Medicine and Biomedical Science, University of Sheffield, Western Bank, Sheffield S10 2TN, UK.
- Institute of Molecular Biology and Biotechnology and University of Crete Medical School, Heraklion 71110, Crete, Greece.
- Department of Bioengineering, Nagaoka University of Technology, Nagaoka 940-2188, Japan.
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.
- These authors contributed equally to the work.
Correspondence to: Zhi-Cheng Xiao1,2,12 e-mail: xiao.zhi.cheng@sgh.com.sg
Correspondence to: Gavin S. Dawe11 e-mail: gavindawe@nus.edu.sg
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