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
Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673.
Nat Cell Biol. 2008 Mar;10(3):283-94. doi: 10.1038/ncb1690. Epub 2008 Feb 17.
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.
淀粉样前体蛋白（APP）细胞内结构域（AICD）的释放可能由细胞外信号通过γ-分泌酶依赖性切割触发。AICD与Fe65结合，这可能在AICD依赖性信号传导中起作用；然而，功能性配体尚未得到表征。在本研究中，我们确定TAG1为APP的功能性配体。我们发现，通过与APP的细胞外相互作用，TAG1增加了AICD的释放，并以γ-分泌酶依赖性方式触发了Fe65依赖性活性。TAG1、APP和Fe65在胎儿脑室区的神经干细胞微环境中共定位。来自TAG1-/-、APP-/-和TAG1-/-;APP-/-小鼠的神经前体细胞具有异常增强的神经发生，在TAG1-/-小鼠中，TAG1或AICD可显著逆转这种情况，但Fe65结合位点突变的AICD则不能。值得注意的是，TAG1降低了Fe65+/+小鼠的正常神经发生。Fe65-/-小鼠中也出现了异常增强的神经发生，但不能被TAG1逆转。这些结果描述了一种通过Fe65负向调节神经发生的TAG1-APP信号通路。
