Petri Rebecca, Pircs Karolina, Jönsson Marie E, Åkerblom Malin, Brattås Per Ludvik, Klussendorf Thies, Jakobsson Johan
Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, Lund, Sweden.
Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, Lund, Sweden
EMBO J. 2017 May 15;36(10):1379-1391. doi: 10.15252/embj.201695235. Epub 2017 Mar 23.
During adult neurogenesis, newly formed olfactory bulb (OB) interneurons migrate radially to integrate into specific layers of the OB Despite the importance of this process, the intracellular mechanisms that regulate radial migration remain poorly understood. Here, we find that microRNA (miRNA) let-7 regulates radial migration by modulating autophagy in new-born neurons. Using Argonaute2 immunoprecipitation, we performed global profiling of miRNAs in adult-born OB neurons and identified let-7 as a highly abundant miRNA family. Knockdown of let-7 in migrating neuroblasts prevented radial migration and led to an immature morphology of newly formed interneurons. This phenotype was accompanied by a decrease in autophagic activity. Overexpression of Beclin-1 or TFEB in new-born neurons lacking let-7 resulted in re-activation of autophagy and restored radial migration. Thus, these results reveal a miRNA-dependent link between autophagy and adult neurogenesis with implications for neurodegenerative diseases where these processes are impaired.
在成体神经发生过程中，新形成的嗅球（OB）中间神经元沿径向迁移，以整合到OB的特定层中。尽管这一过程很重要，但调节径向迁移的细胞内机制仍知之甚少。在这里，我们发现微小RNA（miRNA）let-7通过调节新生神经元中的自噬来调节径向迁移。利用AGO2免疫沉淀技术，我们对成年新生OB神经元中的miRNA进行了全面分析，并确定let-7是一个高度丰富的miRNA家族。在迁移的神经母细胞中敲低let-7可阻止径向迁移，并导致新形成的中间神经元形态不成熟。这种表型伴随着自噬活性的降低。在缺乏let-7的新生神经元中过表达Beclin-1或TFEB可导致自噬重新激活并恢复径向迁移。因此，这些结果揭示了自噬与成体神经发生之间的miRNA依赖性联系，这对这些过程受损的神经退行性疾病具有重要意义。
