title: A TAG1-APP signalling pathway through Fe65 negatively modulates neurogenesis.
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.
authors.affiliation: Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673.
authors.forename: Quan-Hong
authors.initials: QH
authors.lastname: Ma
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Futagawa
authors.forename: Wu-Lin
authors.initials: WL
authors.lastname: Yang
authors.forename: Xiao-Dan
authors.initials: XD
authors.lastname: Jiang
authors.forename: Li
authors.initials: L
authors.lastname: Zeng
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Takeda
authors.forename: Ru-Xiang
authors.initials: RX
authors.lastname: Xu
authors.forename: Dominique
authors.initials: D
authors.lastname: Bagnard
authors.forename: Melitta
authors.initials: M
authors.lastname: Schachner
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Furley
authors.forename: Domna
authors.initials: D
authors.lastname: Karagogeos
authors.forename: Kazutada
authors.initials: K
authors.lastname: Watanabe
authors.forename: Gavin S
authors.initials: GS
authors.lastname: Dawe
authors.forename: Zhi-Cheng
authors.initials: ZC
authors.lastname: Xiao
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism* / Q000502:physiology*; D058969:Contactin 2; D006224:Cricetinae; D003412:Cricetulus; D005786:Gene Expression Regulation; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; C486243:Apbb1 protein, mouse; D015816:Cell Adhesion Molecules, Neuronal; C548675:Cntn2 protein, mouse; D058969:Contactin 2; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D053829:Amyloid Precursor Protein Secretases