title: Presenilin-dependent receptor processing is required for axon guidance.
abstract: The Alzheimer's disease-linked gene presenilin is required for intramembrane proteolysis of amyloid-β precursor protein, contributing to the pathogenesis of neurodegeneration that is characterized by loss of neuronal connections, but the role of Presenilin in establishing neuronal connections is less clear. Through a forward genetic screen in mice for recessive genes affecting motor neurons, we identified the Columbus allele, which disrupts motor axon projections from the spinal cord. We mapped this mutation to the Presenilin-1 gene. Motor neurons and commissural interneurons in Columbus mutants lacking Presenilin-1 acquire an inappropriate attraction to Netrin produced by the floor plate because of an accumulation of DCC receptor fragments within the membrane that are insensitive to Slit/Robo silencing. Our findings reveal that Presenilin-dependent DCC receptor processing coordinates the interplay between Netrin/DCC and Slit/Robo signaling. Thus, Presenilin is a key neural circuit builder that gates the spatiotemporal pattern of guidance signaling, thereby ensuring neural projections occur with high fidelity.
authors.affiliation: The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Ge
authors.initials: G
authors.lastname: Bai
authors.forename: Onanong
authors.initials: O
authors.lastname: Chivatakarn
authors.forename: Dario
authors.initials: D
authors.lastname: Bonanomi
authors.forename: Karen
authors.initials: K
authors.lastname: Lettieri
authors.forename: Laura
authors.initials: L
authors.lastname: Franco
authors.forename: Caihong
authors.initials: C
authors.lastname: Xia
authors.forename: Elke
authors.initials: E
authors.lastname: Stein
authors.forename: Le
authors.initials: L
authors.lastname: Ma
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Lewcock
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Pfaff
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D002642:Chick Embryo; D006023:Glycoproteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009414:Nerve Growth Factors / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000075388:Netrin-1; D019636:Neurodegenerative Diseases / Q000378:metabolism; D055495:Neurogenesis; D009474:Neurons / Q000378:metabolism; D053763:Presenilins / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000097905:Roundabout Proteins
chemical_list: D006023:Glycoproteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D000075388:Netrin-1; D053763:Presenilins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D025521:Tumor Suppressor Proteins; D000097905:Roundabout Proteins; C120566:slit protein, vertebrate