let-7 regulates radial migration of newborn neurons through positive regulation of autophagy

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. Overall design: Small RNA sequencing data from Argonaute2-RIPseq on newborn neurons of the olfactoy bulb from LV.GFP-AGO2 and sham-injected control mice.

在成体神经发生过程中，新生的嗅球中间神经元（olfactory bulb，OB）会通过径向迁移整合至嗅球的特定层中。尽管该过程具有重要意义，但调控径向迁移的细胞内分子机制仍未被充分阐明。本研究发现，微小RNA（microRNA，miRNA）let-7可通过调控新生神经元的自噬水平，进而调控径向迁移过程。通过Argonaute2免疫沉淀（Argonaute2-immunoprecipitation）技术，我们对成体新生嗅球神经元中的miRNA进行了全局表达谱分析，并鉴定出let-7是一类高丰度的miRNA家族。在迁移中的成神经细胞中敲低let-7，会阻断径向迁移过程，并导致新生中间神经元呈现未成熟的形态，该表型伴随自噬活性的降低。在缺失let-7的新生神经元中过表达Beclin-1或TFEB，可重新激活自噬过程并恢复径向迁移能力。综上，本研究结果揭示了一条依赖于miRNA的自噬与成体神经发生之间的调控通路，该发现可为自噬及成体神经发生过程受损的神经退行性疾病研究提供理论参考。实验整体设计：取自LV.GFP-AGO2病毒转染及假注射对照小鼠的嗅球新生神经元的Argonaute2免疫沉淀测序（Argonaute2-RIPseq）小RNA测序数据。