Amyloid Precursor Protein Regulates Netrin-1-mediated Commissural Axon Outgrowth |
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Authors: | Nicolas Rama David Goldschneider Véronique Corset Jérémy Lambert Laurent Pays Patrick Mehlen |
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Affiliation: | From the Apoptosis, Cancer and Development Laboratory, Equipe labellisée 'La Ligue,' Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France. |
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Abstract: | The multifunctional protein netrin-1 was initially discovered as the main attractive cue for commissural axon guidance by acting through its receptor DCC. Recently, we have shown that netrin-1 also interacts with the orphan transmembrane receptor amyloid precursor protein (APP). APP is cleaved by proteases, generating amyloid-β peptide, the main component of the amyloid plaques that are associated with Alzheimer disease. Our previous work demonstrated that via its interaction with APP, netrin-1 is a negative regulator of amyloid-β production in adult brain, but the biological relevance of APP/netrin-1 interaction under non-pathological conditions was unknown. We show here that during commissural axon navigation, APP, expressed at the growth cone, is part of the DCC receptor complex mediating netrin-1-dependent axon guidance. APP interacts with DCC in the presence of netrin-1 and enhances netrin-1-mediated DCC intracellular signaling, such as MAPK activation. Inactivation of APP in mice is associated with reduced commissural axon outgrowth. Thus, APP functionally acts as a co-receptor for DCC to mediate axon guidance. |
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Keywords: | Amyloid Precursor Protein Axon Cell Signaling MAP Kinases (MAPKs) Neurons DCC Netrin-1 |
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