Inhibition of the Schizophrenia-Associated MicroRNA miR-137 Disrupts Nrg1α Neurodevelopmental Signal Transduction

Cell Reports

Qiaochu Gu¹  Arielle Nicole Valdez¹  Stephanie Elaine Zimmer¹  Kristen Therese Thomas¹  Bart Russell Anderson¹  Daniel Hawkins¹  Niraj Shah¹  Gary Jonathan Bassell¹ 

[1] Department of Cell Biology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA;

关键词: miR-137;    neuregulin;    BDNF;    schizophrenia;    mTOR;    AMPAR;   

DOI  :  10.1016/j.celrep.2017.06.038

来源: DOAJ

【 摘 要 】

Genomic studies have repeatedly associated variants in the gene encoding the microRNA miR-137 with increased schizophrenia risk. Bioinformatic predictions suggest that miR-137 regulates schizophrenia-associated signaling pathways critical to neural development, but these predictions remain largely unvalidated. In the present study, we demonstrate that miR-137 regulates neuronal levels of p55γ, PTEN, Akt2, GSK3β, mTOR, and rictor. All are key proteins within the PI3K-Akt-mTOR pathway and act downstream of neuregulin (Nrg)/ErbB and BDNF signaling. Inhibition of miR-137 ablates Nrg1α-induced increases in dendritic protein synthesis, phosphorylated S6, AMPA receptor subunits, and outgrowth. Inhibition of miR-137 also blocks mTORC1-dependent responses to BDNF, including increased mRNA translation and dendritic outgrowth, while leaving mTORC1-independent S6 phosphorylation intact. We conclude that miR-137 regulates neuronal responses to Nrg1α and BDNF through convergent mechanisms, which might contribute to schizophrenia risk by altering neural development.

【 授权许可】

Unknown