Role of miR-146a in mouse brain development: relevance for developmental brain disorders

MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression post-transcriptionally. miRs are involved in a wide range of regulation networks, including those involved in brain development. We and other showed an upregulation of miR-146a in autism spectrum disorders, intellectual disability and epilepsy. Taking advantage of a mouse model constitutively inactivated for miR-146a, we investigated its functions during brain development using a combination of imaging, molecular, cell biology techniques and behavioral studies. We demonstrated that loss of miR-146a causes time and region specific expression defects in the mouse brain. Pyramidal and interneurons are the most severely affected cell types with deregulated pathways reflecting different stages of neuronal differentiation and synaptic maturation. We showed that absence of miR-146a impairs the balance between proliferation and differentiation of neural progenitors. We observed no difference in neither brain weight nor total volume but an increased hemispheric asymmetry of hippocampal volume. Lastly, impaired associative memory was also observed. Our results show that miR-146 is important for proper brain development and support the hypothesis that miR-146a deregulation may play a role in developmental brain disorders. Overall design: We tested the neocortex at E14.5. For P30 and P6 stages, we tested the amygdala, hippocampus and sensoricortex. Each region was sampled at least 3 times (per genotype) from mice born to different moms.微小RNA（MicroRNAs, miRNAs）是一类短小的非编码RNA，可在转录后水平调控基因表达。此类RNA参与了广泛的基因调控网络，其中包括与大脑发育相关的通路。本研究团队与其他学者均已证实，miR-146a在自闭症谱系障碍、智力障碍与癫痫患者体内存在表达上调现象。本研究利用miR-146a组成型灭活的小鼠模型，结合成像技术、分子生物学技术、细胞生物学技术与行为学实验，探究了该RNA在大脑发育过程中的功能。研究证实，miR-146a的缺失会导致小鼠大脑出现时间特异性与区域特异性的表达异常。锥体神经元与中间神经元是受影响最严重的细胞类型，其调控通路的失调反映了神经元分化与突触成熟的不同阶段出现紊乱。本研究发现，miR-146a的缺失会损害神经祖细胞的增殖与分化平衡。实验未观察到小鼠脑重量及总体积存在明显异常，但海马体体积的半球间不对称性显著升高。此外，本研究还观测到小鼠的关联记忆功能受损。本研究结果表明，miR-146对于大脑的正常发育至关重要，同时支持了"miR-146a表达失调可能参与脑部发育障碍发生"这一假说。 整体实验设计：我们于胚胎发育第14.5天（E14.5）采集小鼠新皮层样本；对于出生后第6天（P6）与第30天（P30）的样本，我们分别采集了杏仁核、海马体与感觉皮层。每个脑区均从不同母鼠所产的子代小鼠中采样，且每个基因型组至少重复采样3次。