title: Bicaudal-D1 regulates the intracellular sorting and signalling of neurotrophin receptors.
abstract: We have identified a new function for the dynein adaptor Bicaudal D homolog 1 (BICD1) by screening a siRNA library for genes affecting the dynamics of neurotrophin receptor-containing endosomes in motor neurons (MNs). Depleting BICD1 increased the intracellular accumulation of brain-derived neurotrophic factor (BDNF)-activated TrkB and p75 neurotrophin receptor (p75(NTR)) by disrupting the endosomal sorting, reducing lysosomal degradation and increasing the co-localisation of these neurotrophin receptors with retromer-associated sorting nexin 1. The resulting re-routing of active receptors increased their recycling to the plasma membrane and altered the repertoire of signalling-competent TrkB isoforms and p75(NTR) available for ligand binding on the neuronal surface. This resulted in attenuated, but more sustained, AKT activation in response to BDNF stimulation. These data, together with our observation that Bicd1 expression is restricted to the developing nervous system when neurotrophin receptor expression peaks, indicate that BICD1 regulates neurotrophin signalling by modulating the endosomal sorting of internalised ligand-activated receptors.
authors.affiliation: Molecular NeuroPathobiology Laboratory, Cancer Research UK London Research Institute, London, UK giampietro.schiavo@ucl.ac.uk marco.terenzio@weizmann.ac.il.
authors.forename: Marco
authors.initials: M
authors.lastname: Terenzio
authors.affiliation: Molecular NeuroPathobiology Laboratory, Cancer Research UK London Research Institute, London, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Golding
authors.affiliation: Electron Microscopy Laboratory, Cancer Research UK London Research Institute, London, UK.
authors.forename: Matthew R G
authors.initials: MR
authors.lastname: Russell
authors.affiliation: Developmental Genetics Laboratory, Cancer Research UK London Research Institute, London, UK.
authors.forename: Krzysztof B
authors.initials: KB
authors.lastname: Wicher
authors.affiliation: Transgenic Services laboratory, Cancer Research UK London Research Institute, London, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Rosewell
authors.affiliation: Experimental Histopathology Laboratory, Cancer Research UK London Research Institute, London, UK.
authors.forename: Bradley
authors.initials: B
authors.lastname: Spencer-Dene
authors.affiliation: Developmental Genetics Laboratory, Cancer Research UK London Research Institute, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Ish-Horowicz
authors.affiliation: Molecular NeuroPathobiology Laboratory, Cancer Research UK London Research Institute, London, UK Sobell Department of Motor Neuroscience & Movement Disorders, UCL-Institute of Neurology, University College London, London, UK giampietro.schiavo@ucl.ac.uk marco.terenzio@weizmann.ac.il.
authors.forename: Giampietro
authors.initials: G
authors.lastname: Schiavo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D008164:Luminescent Proteins; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008954:Models, Biological; D009046:Motor Neurons / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D000097573:Red Fluorescent Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019208:Brain-Derived Neurotrophic Factor; D003598:Cytoskeletal Proteins; D008164:Luminescent Proteins; D034741:RNA, Small Interfering; D017475:Receptors, Nerve Growth Factor; D000097573:Red Fluorescent Protein; C000591599:Bicd1 protein, mouse
keywords: Bicd1; TrkB; intracellular sorting; neurotrophin signalling; p75NTR