A TAG1-APP signalling pathway through Fe65 negatively modulates neurogenesis

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

来源：Nature Cell Biology, 2008, 10(3): 283-U29.

DOI：10.1038/ncb1690

• AMYLOID PRECURSOR PROTEIN
• DEPENDENT TRANSCRIPTIONAL CONTROL
• DEGRADING ENZYME NEPRILYSIN
• REGULATED INTRAMEMBRANE PROTEOLYSIS
• CARBOXYL-TERMINAL DOMAIN
• PIQUARD ET-AL.
• ALZHEIMERS-DISEASE
• INTRACELLULAR DOMAIN
• A-BETA
• ADHESION MOLECULES

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 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.

• 出版日期2008-3
• 单位南方医科大学; rutgers