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 γ-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 γ-secretasedependent 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.The γ-secretase proteolytic complex cleaves a wide spectrum of type-1 transmembrane protein substrates, including Notch and APP, by regulated intramembrane proteolysis (RIP) to release their intracellular domains 1 . Ligand-binding to the substrate protein is one mechanism by which this cleavage is regulated. When a ligand binds to Notch, RIP stimulates the release of the intracellular domain of Notch (NICD), which interacts with the transcription factor CSL (CBF1, Suppressor of Hairless and Lag1; ref. 1). Similar transcriptional activity or regulation has been proposed for the intracellular domains cleaved from other γ-secretase substrates, including AICD, which is cleaved from APP 1 . It is therefore important to understand the physiological mechanisms regulating cleavage of AICD.Glycophosphatidylinositol (GPI)-linked proteins are anchored to the outer leaflet of the plasma membrane and mediate the dynamic remodelling of membranes during cell-cell interactions. In the central nervous system (CNS), GPI-linked recognition molecules, such as TAG1, NB-3 and F3, have been implicated in key developmental events, including selective axonal fasciculation, neural cell adhesion and migration, and neurite outgrowth 2 . Recently, we identified F3 and its homologue NB-3 as functional ligands for the Notch receptor and we showed that their interaction with each other is involved in oligodendrocyte differentiation through activation of the transcriptional factor Deltex1 (refs 3, 4). Given that RIP processing of APP is strikingly similar to that of the Notch receptor 5 , knowledge of the interaction between F3 and the Notch receptor has led us to ask whether members of the F3 family may act as APP ligands. RESULTS TAG1 and APP bind to each otherTo investigate the potential interaction between APP and members of the F3 subfamily, cell adhesion assays were performed. When F3-transfected CHO (CHOF3) cells or non-transfected CHO cells were seeded onto c...

Fe65 matters: New light on an old molecule

“…Indeed, they show learning and memory impairment and defective early-phase LTP at the Shaffer collateral-CA1 synapses (28). Moreover, Fe65 null mice show enhanced neurogenesis (29), similar to that observed in APP2/2 mice, as well as a slight increase of GnRH-1 neurons during development (30). In another set of experiments, it was demonstrated that Fe65 null mice are more sensitive to DNA-damaging agents, as etoposide and ionizing radiations (31).…”

Altered neurogenesis in mouse models of Alzheimer disease

“…This confirms that AICD is able to act as a negative modulator of neurogenesis as one of its potential physiologic functions. 49 Ts65Dn mice show a defective responsiveness to Shh, representing an important mitogen responsible for controlling cell division during neurodevelopment. Trisomic neural precursor cells derived from Ts65Dn mice have been demonstrated to exhibit increased expression levels of the Shh receptor Ptch1, resulting in suppression of Smoothend (Smo), a second receptor involved in this signaling pathway.…”

Amyloid precursor protein at node of Ranvier modulates nodal formation

“…The specificity of APP antibody was tested previously and confirmed by lack of immunoreactivity in APP KO mice. [15][16][17][18] These observations demonstrate that axonal APP is a novel component of the NORs and its clustering occurs specifically in the CNS, but not in the PNS.…”

“…30 APP also plays a role in cell adhesion and interacts with various cell adhesion molecules, [31][32][33] including TAG-1/ TAX. 17 Previously, it has been noted that APP expression in axons is upregulated on neural injury, and hence, APP expression has been utilized as a marker for axonal degeneration. 7 Moreover, following demyelinating injury, APP expression was also increased.…”