The amyloid precursor protein is a conserved Wnt receptor

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.

The Drosophila RNA binding protein Nab2 patterns dendritic arbors and axons via the planar cell polarity pathway

“…2010), the neuron-specific PCP modulator Appl (S ingh and M lodzik 2012; S oldano et al . 2013; L iu et al . 2021), the anchoring protein Akap200 (J ackson and B erg 2002; W eber et al .…”

“…While neuronal Nab2 protein is primarily nuclear (PAK et al 2011), the protein is also detected in cytoplasmic messenger ribonucleoprotein S1). Appl acts as a downstream neuronalspecific effector of the PCP pathway (SOLDANO et al 2013;LIU et al 2021) and elevated Appl protein in response to Nab2 loss could be an indirect consequence of altered core PCP pathway activity or evidence of direct regulation of the Appl transcript. These differing interactions illustrate the complexity of RBP function across a neuron with specific interactions affecting sub-cellular compartments in different ways.…”

“…Our previous work established genetic interactions between Nab2 and an array of PCP/Wnt alleles in the adult Drosophila eye (LEE et al 2020). Here, we focused on three of these factors: the core PCP/Wnt factor Vang, which proteomic data indicate is reduced 5-fold in Nab2 ex3 brains (CORGIAT et al 2021), the accessory factor Appl (Amyloid precursor protein-like), which is a proposed PCP/Wnt co-receptor and has established links to neurological disease (SINGH AND SOLDANO et al 2013;LIU et al 2021), and the PCP/Wnt cytoplasmic adaptor Dsh, which also genetically interacts with Nab2 in the wing to control hair polarity (LEE et al 2020). As has been observed in Nab2 ex3 adult brains (KELLY et al 2016;BIENKOWSKI et al 2017), Nab2 ex3 mutant pupal brain at 48-72h APF (after puparium formation) display highly penetrant defects in structure of the α-lobes (85% thinned or missing) and β-lobes (88% fused or missing) as detected by anti-Fas2 staining (Fig.…”

“…Core PCP components signal to downstream effector molecules that exert localized effects on the F-actin cytoskeleton (COURBARD et al 2009;ADLER 2012;SOLDANO et al 2013;FAGAN et al 2014;GOMBOS et al 2015), which in turn guides epithelial traits like proximal-distal wing hair orientation in Drosophila and sensory hair cell polarity in the mouse cochlea (JONES AND CHEN 2007;QIAN et al 2007;SIMONS AND MLODZIK 2008;CHACON-HESZELE AND CHEN 2009;RIDA AND CHEN 2009;ALPATOV et al 2014). One such factor is encoded by the β amyloid protein precursor-like (Appl) gene and modulates the PCP pathway during axonal and dendritic outgrowth (SOLDANO et al 2013;LIU et al 2021). Importantly, PCP is required for axon guidance in specific groups of neurons in Drosophila, C. elegans, mice, and chick, and for dendritic branching of mouse cortical and hippocampal neurons, and Drosophila body wall sensory neurons (HINDGES et al 2002;MCLAUGHLIN AND O'LEARY 2005;SCHMITT et al 2006;SHAFER et al 2011;CANG AND FELDHEIM 2013;YOSHIOKA et al 2013;HAGIWARA et al 2014;YASUMURA et al 2021).…”

“…One such factor is encoded by the β amyloid protein precursor-like ( Appl ) gene and modulates the PCP pathway during axonal and dendritic outgrowth (S oldano et al . 2013; L iu et al . 2021).…”