Amyloid Precursor Proteins are neuronal specific modulators of Wnt PCP signaling.

Abstract

Scientific summary Wnt Planar Cell Polarity (PCP) signaling is a universal regulator of polarity in epithelial cells, but it regulates axon outgrowth in neurons, suggesting the existence of axonal modulators of Wnt-PCP activity. The Amyloid precursor proteins (APPs) are intensely investigated because of their link to Alzheimer s disease (AD). APP s in-vivo function in the brain and the mechanisms underlying it remain unclear and controversial. Drosophila possesses a single, neuronal-specific APP homologue called APP Like, or APPL. APPL is expressed in all neurons throughout development, but has no established function in neuronal development. We investigated the role of Drosophila APPL during brain development. We clarified that APPL is involved in the development of the Mushroom Body alfaß neurons and, in particular, is required cell-autonomously for the ß-axons and non-cell autonomously for the alfa-axons growth. Moreover we find that APPL is a modulator of the Wnt-PCP pathway required for axonal outgrowth, but not cell polarity. Molecularly, both human APP and fly APPL bind to PCP receptors, thus suggesting that APPs are part of the membrane protein complex upstream of PCP signaling. Moreover we show that APPL regulates PCP pathway activation by modulating the phosphorylation of the Wnt adaptor protein Dishevelled (Dsh) by Abelson kinase (Abl). Taken together our data support the hypothesis that APPL is the first example of a neuronal-specific modulator of the Wnt-PCP pathway. Furthermore, given the role of APPL in Mushroom Bodies development, we used these neurons as a model to discover more partners of APPL. In particular, using this model, we identified a neuronal-glia communication which is mediated by the genetic interaction between APPL and the NF-KB signaling.nrpages: 125status: publishe