A TAG1-APP signalling pathway through Fe65 negatively modulates neurogenesis.
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.
Ma
Quan-Hong
QH
Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673.
Futagawa
Toshitaka
T
Yang
Wu-Lin
WL
Jiang
Xiao-Dan
XD
Zeng
Li
L
Takeda
Yasuo
Y
Xu
Ru-Xiang
RX
Bagnard
Dominique
D
Schachner
Melitta
M
Furley
Andrew J
AJ
Karagogeos
Domna
D
Watanabe
Kazutada
K
Dawe
Gavin S
GS
Xiao
Zhi-Cheng
ZC
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
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