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

Elizabeth M. McNeill, Chloe Warinner, Stephen Alkins, Alicia Taylor, Hansine Heggeness, Todd F. DeLuca, Tudor A. Fulga, Dennis P. Wall, Leslie C. Griffith and David Vactor ()
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Elizabeth M. McNeill: Harvard Medical School
Chloe Warinner: Harvard Medical School
Stephen Alkins: Brandeis University
Alicia Taylor: Harvard Medical School
Hansine Heggeness: Harvard Medical School
Todd F. DeLuca: Harvard Medical School
Tudor A. Fulga: Harvard Medical School
Dennis P. Wall: Stanford University
Leslie C. Griffith: Brandeis University
David Vactor: Harvard Medical School

Nature Communications, 2020, vol. 11, issue 1, 1-13

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

Date: 2020
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DOI: 10.1038/s41467-020-14761-8

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