miR-51 regulates GABAergic synapses by targeting Rab GEF GLO-4 and lysosomal trafficking-related GLO/AP-3 pathway in Caenorhabditis elegans

Developmental biology

Ping Qiao^2¹  Zhibin Fan^2²  Yinsuo Zhao^3³  Shuai Zhang^1⁴ 

[1] National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China^3;The Department of Cell Biology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China^2;The Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China^4;The Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Changchun 130024, China^1

关键词: GABA;    γ-aminobutyric acid;    PTZ;    pentylenetetrazole;    SNB-1;    Synaptobrevin 1;    GEF;    guaninenucleotide exchange factor;    SVs;    synaptic vesicles;    ACh;    acetylcholine;    NMJs;    neuromuscular junctions;    miRNAs;    microRNAs;    GluR;    glutamate receptor;    nAChR;    neuronal acetylcholine receptor;    MEF-2;    myocyte enhancer factor 2;    Limk1;    Lim-domain-containing protein kinase 1;    LROs;    lysosome-related organelles;    UTR;    untranslated regions;    DNC;    dorsal nerve cord;    RPM-1;    Regulator of presynaptic morphology 1;    miR-51;    GABAergic synapses;    GLO-4;    GLO/AP-3 pathway;   

DOI  :  10.1016/j.ydbio.2018.02.009

学科分类：生物科学（综合）

来源: Academic Press

【 摘 要 】

A deficit of GABA (γ-aminobutyric acid) transmission will lead to epilepsy and other cognitive disorders. Recent evidence has shown that neuronal miRNAs affect various synapses, including GABAergic synapses. However, the miRNAs that control GABAergic synapses remain not fully understood. Here, we identified miR-51, a member of Caenorhabditis elegans miR-99/100 family, as a key regulator of GABAergic synapses. Loss of mir-51 increased PTZ (Pentylenetetrazole) and aldicarb hypersensitivities, and decreased the number of GABAergic synapses and abundance of GABAA receptors. A Rab guaninenucleotide exchange factor (GEF) GLO-4, a well-known component in lysosomal trafficking-related GLO-4/GLO-1/AP-3 (GLO/AP-3) pathway, was discovered to be the direct target of miR-51. Rescue experiments showed that GLO-4 expressed in GABAergic motor neurons functioned as a suppressor of miR-51. Disruption of glo-1 or AP-3 gene apm-3 attenuated the defects of GABAergic synapse in mir-51 mutants, suggesting miR-51 regulated GABAergic synapses through GLO/AP-3 pathway. The present study implies the essential roles of miRNAs on the nervous pathologies characterized by mis-regulated GABA signaling, such as epilepsy.

【 授权许可】

CC BY