title: MicroRNA-8 promotes robust motor axon targeting by coordinate regulation of cell adhesion molecules during synapse development.
abstract: Neuronal connectivity and specificity rely upon precise coordinated deployment of multiple cell-surface and secreted molecules. MicroRNAs have tremendous potential for shaping neural circuitry by fine-tuning the spatio-temporal expression of key synaptic effector molecules. The highly conserved microRNA miR-8 is required during late stages of neuromuscular synapse development in Drosophila. However, its role in initial synapse formation was previously unknown. Detailed analysis of synaptogenesis in this system now reveals that miR-8 is required at the earliest stages of muscle target contact by RP3 motor axons. We find that the localization of multiple synaptic cell adhesion molecules (CAMs) is dependent on the expression of miR-8, suggesting that miR-8 regulates the initial assembly of synaptic sites. Using stable isotope labelling in vivo and comparative mass spectrometry, we find that miR-8 is required for normal expression of multiple proteins, including the CAMs Fasciclin III (FasIII) and Neuroglian (Nrg). Genetic analysis suggests that Nrg and FasIII collaborate downstream of miR-8 to promote accurate target recognition. Unlike the function of miR-8 at mature larval neuromuscular junctions, at the embryonic stage we find that miR-8 controls key effectors on both sides of the synapse. MiR-8 controls multiple stages of synapse formation through the coordinate regulation of both pre- and postsynaptic cell adhesion proteins.
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan.
authors.forename: Cecilia S
authors.initials: CS
authors.lastname: Lu
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhai
authors.affiliation: Department of Zoology, University of Cambridge, Cambridge, UK Max Planck Institute of Neurobiology, Martinsried, Germany.
authors.forename: Alex
authors.initials: A
authors.lastname: Mauss
authors.affiliation: Department of Zoology, University of Cambridge, Cambridge, UK.
authors.forename: Matthias
authors.initials: M
authors.lastname: Landgraf
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Gygi
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan davie_vanvactor@hms.harvard.edu.
authors.forename: David
authors.initials: D
authors.lastname: Van Vactor
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D004330:Drosophila / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism; D007553:Isotope Labeling; D013058:Mass Spectrometry; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D008959:Models, Neurological; D009046:Motor Neurons / Q000502:physiology*; D009469:Neuromuscular Junction / Q000235:genetics / Q000502:physiology; D016133:Polymerase Chain Reaction; D013569:Synapses / Q000378:metabolism / Q000502:physiology*
chemical_list: D015815:Cell Adhesion Molecules; D035683:MicroRNAs; C526630:MIRN8 microRNA, Drosophila
keywords: Drosophila neuromuscular junction; Fasciclin III; Neuroglian; miR-8; microRNA; synapse development