The Drosophila homologue of the amyloid precursor protein is a conserved modulator of Wnt PCP signaling

PLoS Biol. 2013;11(5):e1001562. doi: 10.1371/journal.pbio.1001562. Epub 2013 May 14.

Abstract

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 APP homologue called APP Like, or APPL. APPL is expressed in all neurons throughout development, but has no established function in neuronal development. We therefore investigated the role of Drosophila APPL during brain development. We find that APPL is involved in the development of the Mushroom Body αβ neurons and, in particular, is required cell-autonomously for the β-axons and non-cell autonomously for the α-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 form complexes with 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 suggest that APPL is the first example of a modulator of the Wnt-PCP pathway specifically required for axon outgrowth.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Amyloid beta-Protein Precursor / genetics*
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Cell Polarity
  • Dishevelled Proteins
  • Drosophila / genetics
  • Drosophila / metabolism*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • HEK293 Cells
  • Humans
  • Mushroom Bodies / cytology
  • Mushroom Bodies / metabolism
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism
  • Signal Transduction*
  • Wnt Proteins / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Amyloid beta-Protein Precursor
  • Dishevelled Proteins
  • Drosophila Proteins
  • Phosphoproteins
  • Wnt Proteins
  • dsh protein, Drosophila
  • Protein-Tyrosine Kinases
  • Abl protein, Drosophila

Grant support

This work was supported by VIB (BAH and BDS), Concerted Research Action (GOA) and Methusalem grants from the KU Leuven (BDS and BAH), Fonds Wetenschappelijke Oderzoeks (FWO) grants G.0543.08, G.0680.10, G.0681.10, and G.0503.12 (BAH), grant ANR-07-NEURO-034 from the Agence Nationale pour la Recherche (JMD) and the Czech Science Foundation (grants 204/09/0498, 301/11/0747), Ministry of Education, Youth and Sports of the Czech Republic (grant MSM0021622430), Academy of Sciences of the Czech Republic (AVOZ50040507, AVOZ50040702), and an EMBO Installation Grant (VB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript