RNA helicase MOV10 suppresses fear memory and dendritic arborization and regulates microtubule dynamics in hippocampal neurons [RNA-seq]

RNA helicase MOV10 is highly expressed in postnatal brain and associates with FMRP and AGO2, suggesting a role in translation regulation in learning and memory. We generated a brain-specific knockout mouse (Mov10 Deletion) with greatly reduced MOV10 expression in cortex and hippocampus. Behavior testing revealed enhanced fear memory, similar to that observed in a mouse with reduced brain microRNA production, supporting MOV10s reported role as an AGO2 cofactor. Cultured hippocampal neurons have elongated distal dendrites, a reported feature of augmin/HAUS over-expression in Drosophila da sensory neurons. In mitotic spindle formation, HAUS is antagonized by the microtubule bundling protein NUMA1. Numa1 mRNA is a MOV10 CLIP target and is among the genes significantly decreased in Mov10 Deletion hippocampus. Restoration of NUMA1 expression and knockdown of HAUS rescued microtubule comet formation in dendritic growth cones. This is the first evidence of translation regulation of NUMA1 as a control point in dendritogenesis. We isolated total RNA from hippocampi WT and Mov10 Deletion P0 mice and performed RNA-seq to look at the steady state expression of mRNAs.RNA解旋酶MOV10（RNA helicase MOV10）在出生后大脑中呈高表达，并与FMRP及AGO2（Argonaute 2）相结合，提示其在学习与记忆过程中参与翻译调控。我们构建了脑特异性敲除小鼠（Mov10 Deletion），该小鼠皮层与海马体中的MOV10表达水平显著降低。行为学测试显示，该小鼠的恐惧记忆能力增强，这与脑内微RNA（microRNA）生成减少的小鼠表型相似，佐证了MOV10作为AGO2辅助因子的已有研究结论。体外培养的海马神经元出现远端树突伸长现象，该表型曾在果蝇感觉神经元中因augmin/HAUS过表达而被报道。在有丝分裂纺锤体形成过程中，HAUS可被微管捆绑蛋白NUMA1拮抗。Numa1 mRNA是MOV10的CLIP（交联免疫沉淀）靶标，且在Mov10 Deletion小鼠的海马体中呈显著下调表达。恢复NUMA1的表达或敲低HAUS，均可拯救树突生长锥中的微管彗星（microtubule comet）形成缺陷。这是首次证实NUMA1的翻译调控可作为树突发生过程中的关键调控节点。我们从野生型（WT）与Mov10 Deletion的P0新生小鼠海马体中提取总RNA，并进行RNA测序（RNA-seq），以检测mRNA的稳态表达水平。