The conserved microRNA miR-34 regulates synaptogenesis via coordination of distinct mechanisms in presynaptic and postsynaptic cells

摘要

Micro(mi)RNA-based post-transcriptional regulatory mechanisms have been broadly implicatedin the assembly and modulation of synaptic connections required to shape neuralcircuits, however, relatively few specific miRNAs have been identified that control synapseformation. Using a conditional transgenic toolkit for competitive inhibition of miRNA functionin Drosophila, we performed an unbiased screen for novel regulators of synapse morphogenesisat the larval neuromuscular junction (NMJ). From a set of ten new validated regulatorsof NMJ growth, we discovered that miR-34 mutants display synaptic phenotypes andcell type-specific functions suggesting distinct downstream mechanisms in the presynapticand postsynaptic compartments. A search for conserved downstream targets for miR-34identified the junctional receptor CNTNAP4/Neurexin-IV (Nrx-IV) and the membranecytoskeletal effector Adducin/Hu-li tai shao (Hts) as proteins whose synaptic expression isrestricted by miR-34. Manipulation of miR-34, Nrx-IV or Hts-M function in motor neurons ormuscle supports a model where presynaptic miR-34 inhibits Nrx-IV to influence active zoneformation, whereas, postsynaptic miR-34 inhibits Hts to regulate the initiation of boutonformation from presynaptic terminals.