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The Amyloid Precursor Protein Is a Conserved Receptor for Slit to Mediate Axon Guidance
- Source :
- eNeuro
- Publication Year :
- 2017
-
Abstract
- 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 inCaenorhabditiselegans 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.
- Subjects :
- rac1 GTP-Binding Protein
receptor
amyloid precursor protein
corpus callosum
Amyloid beta-Protein Precursor
0302 clinical medicine
Pioneer axon
Amyloid precursor protein
Receptors, Immunologic
Caenorhabditis elegans
Cerebral Cortex
Neurons
0303 health sciences
biology
axon guidance
General Neuroscience
Nuclear Proteins
3.1
General Medicine
New Research
Ligand (biochemistry)
Slit
Ectodomain
Intercellular Signaling Peptides and Proteins
RNA Interference
Alzheimer’s disease
mice
Nerve Tissue Proteins
explant culture
03 medical and health sciences
mental disorders
Animals
Humans
Caenorhabditis elegans Proteins
030304 developmental biology
biology.organism_classification
Embryo, Mammalian
Mice, Inbred C57BL
HEK293 Cells
Membrane protein
Animals, Newborn
p21-Activated Kinases
biology.protein
Axon guidance
Disorders of the Nervous System
Nerve Net
Neuroscience
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 23732822
- Volume :
- 4
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- eNeuro
- Accession number :
- edsair.doi.dedup.....1a2e734a8d87445cea737e84c6679e2a