Amyloid precursor protein regulates netrin-1-mediated commissural axon outgrowth.
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.
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.
Nicolas
N
Rama
David
D
Goldschneider
Véronique
V
Corset
Jérémy
J
Lambert
Laurent
L
Pays
Patrick
P
Mehlen
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000075389:DCC Receptor; D020439:Growth Cones / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D000075388:Netrin-1; D059748:Proteolysis; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D000075389:DCC Receptor; C501910:Dcc protein, mouse; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1