RT Journal Article SR Electronic T1 The Amyloid Precursor Protein Is a Conserved Receptor for Slit to Mediate Axon Guidance JF eneuro JO eNeuro FD Society for Neuroscience SP ENEURO.0185-17.2017 DO 10.1523/ENEURO.0185-17.2017 VO 4 IS 3 A1 Baiping Wang A1 Hongmei Li A1 Sena A. Mutlu A1 Devon A. Bowser A1 Michael J. Moore A1 Meng C. Wang A1 Hui Zheng YR 2017 UL http://www.eneuro.org/content/4/3/ENEURO.0185-17.2017.abstract AB The amyloid precursor protein (APP) is a receptor-like membrane protein. Although APP processing and β-amyloid production play a central role in Alzheimer’s disease (AD) pathogenesis, the physiological function of APP remains elusive. Here, we identify APP as a novel receptor for Slit that mediates axon guidance and neural circuit formation. APP deficiency abolishes the Slit repulsive effect in a 3D olfactory explant culture, consistent with its callosal projection deficit in vivo and reminiscent of Slit loss. Inactivation of APP ortholog APL-1 in Caenorhabditis elegans results in pioneer axon mistargeting and genetic analysis places APL-1 in the SLT-1 (Slit)/SAX-3 (Robo) repulsive pathway. Slit binds to APP through the E1 domain, which triggers APP ectodomain shedding and recruitment of the intracellular FE65 and Pak1 complex and associated Rac1 GTPase activation. Our study establishes APP as a novel receptor for Slit ligand mediating axon guidance and neural circuit formation.