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Nicolas M.,Center for the Biology of Disease | Nicolas M.,University of Leuven Group Biomedicine | Hassan B.A.,Center for the Biology of Disease | Hassan B.A.,University of Leuven Group Biomedicine
Development (Cambridge) | Year: 2014

Interest in the amyloid precursor protein (APP) has increased in recent years due to its involvement in Alzheimer's disease. Since its molecular cloning, significant genetic and biochemical work has focused on the role of APP in the pathogenesis of this disease. Thus far, however, these studies have failed to deliver successful therapies. This suggests that understanding the basic biology of APP and its physiological role during development might be a crucial missing link fora better comprehension of Alzheimer's disease. Here, we present an overview of some of the key studies performed in various model organisms that have revealed roles for APP at different stages of neuronal development. © 2014. Published by The Company of Biologists Ltd. Source


Soldano A.,Center for the Biology of Disease | Soldano A.,University of Leuven Group Biomedicine | Okray Z.,Center for the Biology of Disease | Okray Z.,University of Leuven Group Biomedicine | And 14 more authors.
PLoS Biology | Year: 2013

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. © 2013 Soldano et al. Source


Zschatzsch M.,Center for the Biology of Disease | Zschatzsch M.,University of Leuven Group Biomedicine | Oliva C.,Center for the Biology of Disease | Langen M.,Center for the Biology of Disease | And 14 more authors.
eLife | Year: 2014

Axonal branching allows a neuron to connect to several targets, increasing neuronal circuit complexity. While axonal branching is well described, the mechanisms that control it remain largely unknown. We fnd that in the Drosophila CNS branches develop through a process of excessive growth followed by pruning. In vivo high-resolution live imaging of developing brains as well as loss and gain of function experiments show that activation of Epidermal Growth Factor Receptor (EGFR) is necessary for branch dynamics and the fnal branching pattern. Live imaging also reveals that intrinsic asymmetry in EGFR localization regulates the balance between dynamic and static flopodia. Elimination of signaling asymmetry by either loss or gain of EGFR function results in reduced dynamics leading to excessive branch formation. In summary, we propose that the dynamic process of axon branch development is mediated by differential local distribution of signaling receptors. © Zschätzsch et al. Source

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