The Amyloid Precursor Protein (APP) and its homologues are transmembrane proteins required for various aspects of neuronal development and activity, whose molecular function is unknown. Specifically, it is unclear whether APP acts as a receptor, and if so what its ligand(s) may be. We show that APP binds the Wnt ligands Wnt3a and Wnt5a and that this binding regulates APP protein levels. Wnt3a binding promotes full-length APP (flAPP) recycling and stability. In contrast, Wnt5a promotes APP targeting to lysosomal compartments and reduces flAPP levels. A conserved Cysteine-Rich Domain (CRD) in the extracellular portion of APP is required for Wnt binding, and deletion of the CRD abrogates the effects of Wnts on flAPP levels and trafficking. Finally, loss of APP results in increased axonal and reduced dendritic growth of mouse embryonic primary cortical neurons. This phenotype can be cell-autonomously rescued by full length, but not CRD-deleted, APP and regulated by Wnt ligands in a CRD-dependent manner.

The amyloid precursor protein is a conserved Wnt receptor / Liu, Tengyuan; Zhang, Tingting; Nicolas, Maya; Boussicault, Lydie; Rice, Heather; Soldano, Alessia; Claeys, Annelies; Petrova, Iveta; Fradkin, Lee; De Strooper, Bart; Potier, Marie-Claude; Hassan, Bassem A. - In: ELIFE. - ISSN 2050-084X. - 10:(2021), pp. 691901-691926. [10.7554/eLife.69199]

The amyloid precursor protein is a conserved Wnt receptor

Soldano, Alessia;
2021-01-01

Abstract

The Amyloid Precursor Protein (APP) and its homologues are transmembrane proteins required for various aspects of neuronal development and activity, whose molecular function is unknown. Specifically, it is unclear whether APP acts as a receptor, and if so what its ligand(s) may be. We show that APP binds the Wnt ligands Wnt3a and Wnt5a and that this binding regulates APP protein levels. Wnt3a binding promotes full-length APP (flAPP) recycling and stability. In contrast, Wnt5a promotes APP targeting to lysosomal compartments and reduces flAPP levels. A conserved Cysteine-Rich Domain (CRD) in the extracellular portion of APP is required for Wnt binding, and deletion of the CRD abrogates the effects of Wnts on flAPP levels and trafficking. Finally, loss of APP results in increased axonal and reduced dendritic growth of mouse embryonic primary cortical neurons. This phenotype can be cell-autonomously rescued by full length, but not CRD-deleted, APP and regulated by Wnt ligands in a CRD-dependent manner.
2021
10
691901
691926
e691926
10.7554/eLife.69199
https://elifesciences.org/articles/69199
Liu, Tengyuan; Zhang, Tingting; Nicolas, Maya; Boussicault, Lydie; Rice, Heather; Soldano, Alessia; Claeys, Annelies; Petrova, Iveta; Fradkin, Lee; De Strooper, Bart; Potier, Marie-Claude; Hassan, Bassem A
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11767/133250
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