title: The Drosophila homologue of the amyloid precursor protein is a conserved modulator of Wnt PCP signaling.
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.
authors.affiliation: VIB Center for the Biology of Disease, Leuven, Belgium.
authors.forename: Alessia
authors.initials: A
authors.lastname: Soldano
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Okray
authors.forename: Pavlina
authors.initials: P
authors.lastname: Janovska
authors.forename: Kateřina
authors.initials: K
authors.lastname: Tmejová
authors.forename: Elodie
authors.initials: E
authors.lastname: Reynaud
authors.forename: Annelies
authors.initials: A
authors.lastname: Claeys
authors.forename: Jiekun
authors.initials: J
authors.lastname: Yan
authors.forename: Zeynep Kalender
authors.initials: ZK
authors.lastname: Atak
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
authors.forename: Jean-Maurice
authors.initials: JM
authors.lastname: Dura
authors.forename: Vítězslav
authors.initials: V
authors.lastname: Bryja
authors.forename: Bassem A
authors.initials: BA
authors.lastname: Hassan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D016764:Cell Polarity; D000072261:Dishevelled Proteins; D004330:Drosophila / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D024521:Mushroom Bodies / Q000166:cytology / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; D000072261:Dishevelled Proteins; D029721:Drosophila Proteins; D010750:Phosphoproteins; D051153:Wnt Proteins; C000606588:dsh protein, Drosophila; D011505:Protein-Tyrosine Kinases; C506548:Abl protein, Drosophila