<i>Mir505-3p</i> regulates axonal development via inhibiting the autophagy pathway by targeting <i>Atg12</i>

In addition to the canonical role in protein homeostasis, autophagy has recently been found to be involved in axonal dystrophy and neurodegeneration. Whether autophagy may also be involved in neural development remains largely unclear. Here we report that <i>Mir505-3p</i> is a crucial regulator for axonal elongation and branching <i>in vitro</i> and <i>in vivo</i>, through modulating autophagy in neurons. We identify that the key target gene of <i>Mir505-3p</i> in neurons is <i>Atg12</i>, encoding ATG12 (autophagy related 12) which is an essential component of the autophagy machinery during the initiation and expansion steps of autophagosome formation. Importantly, axonal development is compromised in brains of <i>mir505</i> knockout mice, in which autophagy signaling and formation of autophagosomes are consistently enhanced. These results define <i>Mir505-3p</i>-ATG12 as a vital signaling cascade for axonal development via the autophagy pathway, further suggesting the critical role of autophagy in neural development.除了在蛋白质稳态(protein homeostasis)中发挥经典功能外，自噬(autophagy)近年来还被发现与轴突营养不良(axonal dystrophy)及神经退行性变(neurodegeneration)相关。关于自噬是否同样参与神经发育(neural development)，目前仍尚不明确。本研究发现，Mir505-3p可通过调控神经元内的自噬，在体外(in vitro)与体内(in vivo)环境中对轴突伸长与分支起到关键调控作用。我们鉴定出，神经元内Mir505-3p的关键靶基因(target gene)为Atg12，其编码的ATG12（自噬相关12，autophagy related 12）是自噬体形成(autophagosome formation)过程中起始与延伸阶段自噬机器的必需组分。值得注意的是，mir505基因敲除小鼠(knockout mice)的脑组织中轴突发育受损，该模型小鼠的自噬信号通路与自噬体形成均显著增强。本研究结果证实，Mir505-3p-ATG12是一条通过自噬通路调控轴突发育的关键信号级联反应(signaling cascade)，进一步揭示了自噬在神经发育中的重要作用。